Cephalosporin derivatives

ABSTRACT

The present invention relates to novel cephalosporin derivatives, processes for preparing thereof, compositions for preventing and/or treating infectious diseases which comprise the novel cephalosporin derivatives as active components, and the intermediate compounds in the synthesis of cephalosporin derivatives and processes for producing thereof. 
     The novel cephalosporin derivatives according to the present invention contain condensed heterocyclic groups, particularly a triazolopyrimidine ring or a thiadiazolopyrimidine ring as substituents at the 3-position of the cephem skeleton, and a hydroxyimino, an alkyloxyimino or an acyloxyimino moiety as substituents at the 7-position of the cephem skeleton. 
     The compounds of the present invention containing the aforementioned substituents have a strong antibacterial activity against gram-negative bacteria and also against gram-positive bacteria including methicillin-resistant Staphylococcus aureus. These compounds are extremely useful for the treatment of infectious diseases.

BACKGROUND OF THE INVENTION

The present invention relates to novel cephalosporin derivatives,processes for producing the same and compositions containingcephalosporin derivatives for treating and/or preventing infectiousdiseases.

Developments of cephalosporin derivatives have been remarkable. Somecephalosporin derivatives have been developed which have excellentantibacterial activity against gram-negative bacteria. However, theantibacterial activity of these cephalosporin derivatives againstgram-positive bacteria is rather poor. Several cephalosporin antibioticshave been used for the treatment of gram-positive bacteria infectionsand the increase of gram-positive bacteria resistant to cephalosporinantibiotics, for example, methicillin-resistant Staphylococcus aureus(MRSA), has become widely known year by year.

From the foregoing background, it has been desired to developcephalosporin derivatives having a strong antibacterial activity againstgram-positive bacteria while retaining a sufficient antibacterialactivity against gram-negative bacteria.

SUMMARY OF THE INVENTION An object of the present invention is toprovide novel cephalosporin derivatives.

Another object of the present invention is to provide processes forproducing novel cephalosporin derivatives.

A further object of the present invention is to provide compositions forpreventing and/or treating infectious diseases which comprise novelcephalosporin derivatives as active components. A further object of thepresent invention is to provide intermediate compounds in the synthesisof cephalosporin derivatives and processes for producing suchintermediate compounds.

The present invention is based on the selections of groups containingcondensed heterocyclic groups, particularly a triazolopyrimidine ring ora thiadiazolopyrimidine ring, and groups containing an acyloxyiminomoiety as substituents at the 3-position and 7-position of the cephemskeleton, respectively.

The compounds of the present invention containing these substituentshave a wide antibacterial spectrum against gram-negative bacteria andgram-positive bacteria including methicillin-resistant Staphylococcusaureus. These compounds are extremely useful for the treatment ofinfectious diseases.

DETAILED DESCRIPTION OF THE INVENTION

As a result of extensive investigations concerning development ofcephalosporin derivatives having satisfactory anti-bacterial activityagainst gram-negative bacteria and also having strong anti-bacterialactivity against gram positive bacteria, the present inventors havefound that cephalosporin derivatives represented by the general formula(I) satisfy these requirements and, have accomplished the presentinvention.

The present invention is directed to cephalosporin compounds representedby the general formula (I): ##STR1## and salts, hydrates and hydrates ofsalt thereof; wherein R¹ represents a hydrogen atom or anamino-protecting group; Z represents a group represented by: ##STR2##wherein R₂ represents a hydrogen atom, a methyl group, an amino group, acyano group, a hydroxysulfonyl group, a carboxyl group, a carboxymethylgroup, a protected carboxyl group, a methoxycarbonyl group or ahydrazinocarbonyl group, R³ represents a hydrogen atom, a lower alkylgroup having 1 to 3 carbon atoms, a hydroxy group, a methoxy group, acarboxyl group, a carboxymethyl group or a chlorine atom, R⁴ representsa hydrogen atom, a methyl group or a carboxyl group, R⁵ represents ahydrogen atom or a methyl group, R⁶ represents a hydrogen atom, acarboxyl group, an ethoxycarbonyl group or a piperidinocarbonyl group,R⁷ represents a hydrogen atom or a methyl group, R⁸ represents ahydrogen atom or a carboxyl group, R⁹ represents a methyl group, anamino group or a carboxyl group, R¹⁰ represents a hydrogen atom or amethyl group and R¹¹ represents a hydrogen atom or a carboxyl group; R¹²represents a hydrogen atom, a methyl group, a hydroxyl-protecting groupor an acyl group, R¹³ represents a hydrogen atom or acarboxyl-protecting group and the bond represented by a wavy linerepresents a bond of anti-form or syn-form. The present invention isalso directed to a process for preparing the above-describedcephalosporin compounds. The present invention is further directed topharmaceutical compositions for treating and/or preventing infectiousdiseases characterized by containing these cephalosporin derivatives asactive components.

In the cephalosporin derivatives of the present invention represented bygeneral formula (I), it is known that the aminothiazole moiety as thesubstituent at the 7-position thereof exhibits tautomerism as shownbelow: ##STR3## wherein R¹, R¹² and the wavy line have the samesignificance as defined above. In the present invention, theaminothiazole moiety is expressed as including both isomers since bothare generally deemed to be the same substance. Accordingly, thecompounds of the present invention represented by general formula (I)also include both of these tautomeric isomers.

Specific examples of salts of the compounds represented by generalformula (I) include pharmacologically acceptable salts such as alkalimetal salts such as a sodium salt, a potassium salt, etc.; alkalineearth metal salts such as a calcium salt, etc.; salts of organic basessuch as an ammonium salt, a benzylamine salt, a diethylamine salt, etc.;salts of amino acids, such as an arginine salt, a lysine salt, etc.These salts of the compounds may be a mono-salt, a di-salt or atri-salt. In the case of mono-salts or di-salts, the salts may be saltsof the carboxyl group at the 2-position and/or salts of the carboxylgroup contained in the substituents at the 3-position, of the cephemskeleton.

The compounds represented by general formula (I) may form acid additionsalts with pharmacologically acceptable organic or inorganic acids.Typical examples of these salts include salts of inorganic acids such ashydrochlorides, hydrobromides, sulfates, phosphates, etc.; salts oforganic acids such as acetates, citrates, maleates, tartarates,benzoates, ascorbates, ethanosulfonates, toluenesulfonates, etc. Thecompounds of the present invention represented by general formula (I)may be present as a syn-isomer shown below: ##STR4## wherein R¹ and R¹²have the same significance as defined above; or as an anti-isomer shownbelow: ##STR5## wherein R¹ and R¹² have the same significance as definedabove; or as a mixture of these isomers. Among them, the syn-isomer isparticularly preferred and, mixtures mainly composed of the syn-isomerare also preferred.

In the compounds of the present invention represented by general formula(I), the amino-protecting groups may be selected from acyl groups suchas formyl, acetyl, chloroacetyl, t-butoxycarbonyl, benzyloxycarbonyl,etc.; or aralkyl groups such as benzyl, diphenylmethyl, triphenylmethyl,etc. The carboxyl-protecting groups, may be selected from alkyl esterssuch as methyl ester, ethyl ester, etc.; or aralkyl esters such asbenzyl ester, diphenylmethyl ester, triphenylmethyl ester, etc. Specificexamples of hydroxylprotecting groups include aralkyl groups such asbenzyl, etc.; or alkoxyalkyl groups such as methoxymethyl,1-methyl-1-methoxyethyl, etc. Taking into account various operations,synthesis of thus protected products, conditions for removing theprotecting groups, etc. collectively, it is preferred to use atriphenylmethyl group as the amino-protecting group, diphenylmethylester as the carboxyl-protecting group and 1-methyl-1-methoxyethyl asthe hydroxyl-protecting group, respectively.

The compounds of the present invention represented by general formula(I) can be prepared as follows. Namely;

Process A

The compounds of the present invention represented by general formula(I) may be produced by reacting compounds represented by general formula(II): ##STR6## wherein R¹³ and Z have the same significance as definedabove, with compounds represented by general formula (III): ##STR7##wherein R¹, R¹² and the wavy line have the same significance as definedabove.

In this process, the compounds represented by general formula (II) maybe protected, if necessary and desired, at the amino group and/orcarboxyl group thereof with readily removable protecting groups. Thereadily removable protecting group for the amino group and/or carboxylgroup may be for example, a trimethylsilyl group.

The carboxyl group may also be protected by forming salts with inorganicbases such as sodium salts or with organic bases such as triethylaminesalts.

The compounds represented by general formula (II) may also be reactedwith the compounds represented by general formula (III), namely acids,using suitable condensing agents, for example,N,N-dicyclohexylcarbodiimide, N-ethyl-5-phenylisoxazolium-3'-sulfonate,etc. Further, the acids may be converted into appropriate reactivederivatives followed by reacting with the compounds represented bygeneral formula (II).

The appropriate reactive derivatives may be made of, for example, acidhalides (e.g., acid chlorides), azides, acid anhydrides, particularlymixed acid anhydride with strong acids, active esters (e.g.,N-hydroxysuccinimide ester) and active amides (e.g., imidazolide,triazolide).

The reaction between the compounds represented by general formula (II)and the compounds represented by general formula (III) is carried outgenerally in an inert solvent such as an organic solvent, e.g., dioxane,tetrahydrofuran, acetonitrile, chloroform, methylene ,chloride, ethylacetate, dimethylformamide, etc. If necessary the reaction is carriedout, in an aqueous solution, preferably in the presence of deacidifyingagents. As the deacidifying agents, triethylamine, diethylaniline andthe like are employed in the organic solvent system and, in the aqueoussystem, aqueous alkalis, preferably, sodium hydroxide, sodium hydrogencarbonate (sodium bicarbonate), potassium carbonate, etc. are employed.

The reaction may be carried out at temperatures ranging from about -30°C. to room temperature, and preferably from -10° C. to 10° C.

If necessary and desired, the protecting groups may be split off fromthe thus obtained cephalosporin derivatives represented by generalformula (I).

The compounds represented by general formula (II) used in the process ofthe present invention can be prepared by reacting known7-amino-cephalosporanic acid with 2-carboxy-7-mercapto5-methyl-s-triazolo-[1,5-a]pyrimidine (Japanese Patent Application No.247251 1983) or carboxyl-protected derivatives thereof, using as asolvent an organic solvent such as alcohols, dimethylformamide,acetonitrile, etc. or water. In the case that the reaction is carriedout in organic solvents, it is preferred that the reaction be performedin the presence of Lewis acids such as boron trifluoride-ethercomplexes, etc. Further in the case that water is used as the solvent,the reaction can be carried out in the presence of an appropriate amountof aqueous alkalis such as sodium hydrogen carbonate, potassiumcarbonate, etc., or using buffers having a pH of 6.0 to 7.8 as thesolvent. The reaction temperature may be in the range of about 40° C. toabout 80° C., and preferably from 55° C. to 65° C. From the thusobtained compounds represented by general formula (II), the protectinggroups can be split off, if necessary and desired.

Process B

The compounds represented by general formula (I) can be produced byreacting compounds represented by general formula (IV) that can beprepared in a conventional manner: ##STR8## wherein R¹, R¹², R¹³ and thewavy line have the same significance as defined hereinabove, providedthat R¹² does not represent an acyl group, with thiol compoundsrepresented by general formula (V): ##STR9## wherein Z has the samesignificance as defined hereinabove.

The reaction between the compounds represented by general formula (IV)and the compounds represented by general formula (V) can be carried outin organic polar solvents such as alcohol, dimethylformamide, etc. butis preferably carried out in an aqueous system. More preferably, thereaction is carried out in the presence of an appropriate amount ofaqueous alkalis, e.g., sodium hydrogen carbonate or potassium carbonate,bonate, or carried out in a buffer under a pH condition of 6.0 to 7.8.

The reaction in this case can be carried out at temperatures in therange of about 40° C. to about 80° C., and preferably at from 55 to 65°C.

From the thus obtained cephalosporin derivatives represented by generalformula (I), the amino protecting groups thereof can be split off, ifnecessary and desired.

When R¹² represents an acyl group, the compounds represented by generalformula (I) can be prepared as follows.

Process C

The compounds represented by general formula (I) can be produced byreacting compounds represented by general formula (VI): ##STR10##wherein R¹, R¹³, Z and the wavy line have the same significance asdefined hereinabove, with compounds represented by general formula(VII):

    R.sup.12 '--OH                                             (VII)

wherein R¹² ' represents an acyl group.

The reaction can be carried out by reacting the compounds represented bygeneral formula (VII), i.e., the acids, with the compounds representedby general formula (VI), using suitable condensing agents, e.g.,N,N-dicyclohexylcarbodiimide, etc., or by converting the compoundsrepresented by general formula, (VII) into appropriate reactivederivatives, e.g., acid halides, acid anhydrides, or into mixed acidanhydrides which are preferably prepared with strong acids, and thenreacting the derivatives with the compounds represented by generalformula (VI). In view of the reactivity, operability, etc., particularlypreferred is the process in which the compounds represented by generalformula (VII) are converted into the acid halides followed by reactingthe acid halides with the compounds represented by general formula (VI).

The reaction between the compounds represented by general formula (VI)and the compounds represented by general formula (VII) is carried outgenerally in an inert solvent such as an organic solvent, e.g., dioxane,tetrahydrofuran, acetonitrile, chloroform, methylene chloride, ethylacetate, dimethylformamide, etc., or, if desired, in water or a solventmixture of water and organic solvents, preferably in the presence ofdeacidifying agents. As the deacidifying agents, triethylamine,diethylaniline and the like are employed in the organic solvents and, inthe aqueous system, aqueous alkalis, preferably sodium hydroxide, sodiumhydrogen carbonate, potassium carbonate and the like are employed.

The reaction can be conducted at temperatures of about -30° C. to roomtemperature but it is preferred that the reaction be conducted at -10°C. to 10° C.

From the thus obtained cephalosporin derivatives represented by generalformula (I), the protecting groups thereof can be split off, ifnecessary and desired.

The compounds represented by general formula (VI) can be prepared bysplitting the hydroxyl-protecting group off from the products producedin accordance with Process A.

The thiol compounds represented by general formula (V) which areintermediate compounds can be prepared as follows.

Process D

The thiol compounds can be obtained by reacting compounds represented bygeneral formula (VIII):

    X--Z                                                       (VIII)

wherein X represents a halogen atom and Z has the same significance asdefined hereinabove, with sodium hydrogen sulfide. The reaction mayproceed generally in a polar solvent, e.g., alcohol or water, preferablyin an aqueous system. The reaction may also be carried out at roomtemperature or with heating but room temperature is preferred.

Process E

The thiol compounds can also be obtained by reacting compoundsrepresented by generally formula (IX):

    HO--Z                                                      (IX)

wherein Z has the same significance as defined hereinabove, withphosphorus pentasulfide. The reaction can be conducted generally at roomtemperature or with heating in a solvent such as xylene, toluene,pyridine, etc. The reaction is preferably conducted with heating, namelyat about 80°to about 100° C. using pyridine as a solvent.

The 2-amino-4-thiazolyl-2-acyloxyiminoacetic acid derivativesrepresented by general formula (III) which are one of intermediates canbe prepared as follows:

Process F

The acetic acid derivatives can be prepared by reacting known compoundsrepresented by general formula (X): ##STR11## wherein the wavy line hasthe same significance as defined above; R¹ represents a hydrogen atom oran amino protecting group; and R¹⁴ represents a hydrogen atom or acarboxyl protecting group, with compounds represented by general formula(VII):

    R.sup.12 '--OH                                             (VII)

wherein R¹² ' represents an acyl group.

The reaction can be carried out by reacting the compounds represented bygeneral formula (VII), i.e., the acids, with the compounds representedby general formula (X), using suitable condensing agents, e.g.,N,N-dicyclohexylcarbodiimide, etc., or by converting the compoundsrepresented by general formula (VII) into appropriate reactivederivatives, e.g., acid halides, acid anhydrides, or into mixed acidanhydrides which are preferably prepared with strong acids, and thenreacting the derivatives with the compounds represented by generalformula (X). In view of the reactivity, operability, etc., particularlypreferred is the process in which the compounds represented by generalformula (VII) are converted into the acid halides followed by reactingthe acid halides with the compounds represented by general formula (X).

The reaction between the compounds represented by general formula (X)and the compounds represented by general formula (VII) is carried outgenerally in an inert solvent such as an organic solvent, e.g., dioxane,tetrahydrofuran, acetonitrile, chloroform, methylene chloride, ethylacetate, dimethylformamide, etc., or, if desired, in water or in amixture of water and organic solvents, preferably in the presence ofdeacidifying agents. As the deacidifying agents, triethylamine,diethylaniline and the like are employed in the organic solvents and, inthe aqueous system, aqueous alkalis, preferably sodium hydroxide, sodiumhydrogen carbonate, potassium carbonate and the like are employed. Thereaction can be conducted at temperatures ranging from about -30° C. toroom temperature, and preferably from -10° C. to 10° C.

Process G

The acetic acid derivatives can be prepared by reacting compoundsrepresented by genera formula (XI): ##STR12## wherein R¹⁴ represents ahydrogen atom or a carboxyl-protecting group, with compounds representedby general formula (VII):

    R.sup.12 '--OH                                             (VII)

wherein R¹² ' has the same significance as defined hereinabove, in thesame manner as described above and then condensing the resulting productwith thiourea derivatives represented by general formula (XII):##STR13## wherein R¹ has the same significance as defined hereinabove.

In this process, the condensation of the resulting product with thethiourea derivatives can be conducted generally in a solvent such asmethanol, ethanol, tetrahydrofuran, dioxane, methylene chloride,ethylacetate, etc., preferably in the presence of a deacidifying agentsuch as triethylamine, dimethylaniline, potassium carbonate, sodiumhydrogen carbonate, etc. The reaction is carried out at room temperatureor under reflux.

To demonstrate the utility of the compounds of the present invention,data on antibacterial activity of representative compounds are shownbelow.

Compound 1:(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)

oct-2-ene-2-carboxylic acidthio-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

Compound 2:(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo4.2.0]oct-2-ene-2-carboxylic acid

Compound 3:(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(6-carboxy-s-triazolo[1,5-a]pyrimidin-7-yl)-thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

Compound 4:(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(2-carboxymethyl-5-methyl-s-triazolo[l,5-a]-pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.O]oct-2-ene-2-carboxylic acid

Compound 5:(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-](5-carboxymethyl-s-triazolo[l,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

Compound 6:(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(5-carboxy-s-triazolo[1,5-a]pyrimidin-7-yl)-thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

Compound 7:(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(2,6-dicarboxy-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

Compound 8:(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-hydroxyimino)(acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.O]oct-2-ene-2-carboxylic acid

Compound 9:(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-(2-furancarbonyl)oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

Compound 10:(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-(2-thiopenecarbonyl)oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[l,5-a]pyrimidin-7-yl)-thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid

Compound 11:(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-(3-pyridinecarbonyl)oxyimino]acetamido-3-[(2-carboxy-5-methyl-s-trizolo[l,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

Compound 12:(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-(3,4-methylenedioxybenzoyl)oxyimino]-acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

Compound 13:(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-(3,4,5-triacetoxybenzoyl)oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)-thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

Compound 14:(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methylimino)acetamido]-3-[(2-carboxy-s-triazolo[1,5-a]pyrimidin-7-yl)-thiomethyl]8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylicacid

Compound 15:(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(2-carboxy-5-hydroxy-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

Compound 16:(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2(Z-methoxyimino)acetamido]-3-[(5-methoxy-s-triazolo[1,5-a]pyrimidin-7-yl)-thiomethyl]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylicacid

Compound 17:(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(2-amino-5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo [4.2.0]oct-2-ene-2-carboxylic acid

Compound 18:(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(2-hydroxysulfonyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

Compound 19:(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(6-carboxy-7-hydroxy-s-triazolo[1,5-a]pyrimidin-2-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

Compound 20:(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[7-carboxy-3-methyl-s-triazolo[4,3-a]pyrimidin-5-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

Compound 21:(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(7-carboxy-5-hydroxy-s-triazolo[4,3-a]pyrimidin-3-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

Compound 22:(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(7-s-triazolo[1,5-c]pyrimidin-5-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

Compound 23:(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-)Z-methoxyimino)acetamido]-3-[(5-hydroxy-7-methyl-s-triazolo[4,3-c]pyrimidin-3-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

Compound 24:(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(7-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-2-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo4.2.0]oct-2-ene-2-carboxylic acid

Compound 25:(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-benzoyloxyimino)acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

Compound 26:(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-(2-pyrrolecarbonyl)oxyimino]acetamido]-3-[(2-carboxy-5methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

Compound 27:(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-(3,4-diacetoxybenzoyl)oxyimino]-acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[l,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo-[4.2.0.]oct-2-ene-2-carboxylicacid

EXPERIMENTAL EXAMPLE 1

Antibacterial activity in vitro was determined in accordance with theagar plate dilution method.

A platinum loop each of test bacteria (10⁶ cells/ml), cultured inMueller Hinton broth, was inoculated on Mueller Hinton agar plates whichcontained test compounds at various concentrations. After cultivating at37° C. for 20 hours, the minimum inhibitory concentration (MIC μg/ml)was determined.

The results ar shown in Tables 1-a and 1-b.

                                      TABLE 1-a                                   __________________________________________________________________________    (MIC μg/ml)                                                                Com- Staphylococ-                                                                         Escheri-                                                                           Serratia                                                                           Klebsiella                                                                          Proteus                                                                            Pseudomonas                                  pound                                                                              cus aureus                                                                           chia coli                                                                          marcescens                                                                         pneumoniae                                                                          morganii                                                                           aeruginosa                                   Number                                                                             Smith  67   IFO3759                                                                            IFO3317                                                                             IFO3848                                                                            IFO3445                                      __________________________________________________________________________    1    1.57   <0.05                                                                              0.2  <0.05 0.78 50                                           2    1.57   <0.05                                                                              <0.05                                                                              <0.05 0.2  12.5                                         3    12.5   0.39 0.78 <0.05 1.57 >100                                         4    3.13   0.2  0.1  <0.05 0.78 25                                           5    3.13   0.1  0.2  <0.05 0.78 >100                                         6    1.57   <0.05                                                                              0.2  <0.05 0.2  6.25                                         7    12.5   <0.05                                                                              0.39 <0.05 0.39 >100                                         8    0.78   0.2  0.2  <0.05 0.39 >100                                         9    0.39   <0.05                                                                              <0.05                                                                              <0.05 0.2  100                                          10   0.39   0.1  0.1  <0.05 0.39 50                                           11   0.39   <0.05                                                                              <0.05                                                                              <0.05 0.1  >100                                         12   0.78   0.39 0.39 0.39  0.78 25                                           13   0.78   0.05 <0.05                                                                              <0.05 0.2  1.57                                         __________________________________________________________________________

                                      TABLE 1-b                                   __________________________________________________________________________    (MIC μg/ml)                                                                Com- Staphylococ-                                                                         Escheri-                                                                           Serratia                                                                           Klebsiella                                                                          Proteus                                                                            Pseudomonas                                  pound                                                                              cus aureus                                                                           chia coli                                                                          marcescens                                                                         pneumoniae                                                                          morganii                                                                           aeruginosa                                   Number                                                                             Smith  67   IFO3759                                                                            IFO3317                                                                             IFO3848                                                                            IFO3445                                      __________________________________________________________________________    14   3.13   0.1  <0.05                                                                              <0.05 0.2  50                                           15   12.5   0.39 0.1  <0.05 0.78 12.5                                         16   1.57   0.1  0.39 <0.05 3.13 100                                          17   1.57   0.1  0.2  <0.05 0.39 50                                           18   0.39   <0.05                                                                              0.2  <0.05 0.78 100                                          19   6.25   <0.05                                                                              <0.05                                                                              <0.05 0.2  6.25                                         20   3.13   0.2  0.2  <0.05 0.78 12.5                                         21   25     0.78 1.57 0.1   3.13 >100                                         22   1.57   0.1  0.39 <0.05 0.78 50                                           23   3.13   0.1  0.39 <0.05 0.78 50                                           24   0.78   <0.05                                                                              0.2  <0.05 0.39 50                                           25   0.39   0.1  0.1  <0.05 0.39 50                                           26   1.57   0.2  0.2  <0.05 0.78 25                                           27   1.57   <0.05                                                                              <0.05                                                                              <0.05 0.2  0.39                                         __________________________________________________________________________

EXPERIMENTAL EXAMPLE 2

Protection ability against systemic infection was determined as follows.An aqueous suspension of test bacteria was intraperitoneally injectedinto groups of 10 four week old ICR mice. One hour after the infection,test compounds were intravenously administered. The number of survivingmice was counted 1 week after injection to determine the dose at which50% of the test animals were alive (ED₅₀ : mg/kg).

The results are shown in Tables 2-a through 2-b.

                  TABLE 2-a                                                       ______________________________________                                                                       ED.sub.50 (mg/Kg)                                        Escheri-   Klebsiella                                                                              Pseudomonas                                    Compound  chia coli  pneumoniae                                                                              aeruginosa                                     Number    67         IF03317   IF03445                                        ______________________________________                                        1         0.7        0.1       780                                            2         0.8        0.1       360                                            6         0.8        0.1       230                                            ______________________________________                                    

                  TABLE 2-b                                                       ______________________________________                                                         ED.sub.50 (mg/Kg)                                                      Escheri-     Klebsiella                                                                              Staphy-                                      Compound  chia coli    pneumoniae                                                                              lococcus                                     Number    67           IF03317   242*                                         ______________________________________                                        8         --           7.68      3.55                                         9         --           7.68      2.11                                         10        --           --        8.01                                         CEZ       --           --        74                                           ______________________________________                                         *Methicillin-resistant strain                                            

Next, LD₅₀ of representative examples of the compounds of the presentinvention is shown in Table 3 wherein LD₅₀ was determined in accordancewith the Probit method.

                  TABLE 3                                                         ______________________________________                                        Compound No.   LD.sub.50 (mg/Kg)iv                                            ______________________________________                                        1              >1000                                                          2              >1000                                                          6              >1000                                                          8              >1000                                                          9              >1000                                                          10             >1000                                                          ______________________________________                                    

The compounds of the present invention are useful for the treatment ofinfectious diseases caused by gram-positive bacteria such asStaphylococcus aureus, streptococci, etc., or by gram-negative bacteriasuch as Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis,Proteus morganii, Serratia marcescens, Pseudomonas aeruginosa,Citrobacter, Enterobacter, Flavobacter, etc.

The cephalosporin derivatives provided by the present invention can beemployed as pharmaceutical compositions, for example, in the form ofpharmaceutical compositions containing the cephalosporin derivativestogether with appropriate, pharmaceutically acceptable carriers. Thepharmaceutical composition may take a solid form (for example, tablets,capsules, etc.) or a liquid form (for example, injections, etc.). Thecompositions may be sterilized and may contain auxiliary agentsgenerally employed in the pharmaceutical art.

Further, it is preferred to use the compounds after they are formed intofreeze-dried products or powders followed by dissolving them in aconventional solvent, e.g., water or physiological saline, for use. Thecompounds can be used orally or parenterally. While dose variesdepending upon age and conditions of the patient, conditions and kind ofdiseases, etc., from about 0.1 to about 10 g, preferably from about 0.2to about 5 g, can be used as a daily dose for an adult. Parenteraladministration of the compounds provided by the present invention isparticularly preferred.

Hereafter the present invention will be described with reference to theexamples below, but is not deemed to be limited thereto.

EXAMPLE 1

Preparation of 2-carboxy-7-mercapto-5-methyl-s-triazolo[l,5-a]pyrimidine

(Step 1)

Preparation of 7-chloro-2-methoxycarbonyl-5-methyl-s-triazolo[1,5-a]pyrimidine.

7-Hydroxy-2-methoxycarbonyl-5-methyl-s-triazolo-[1,5-a]pyrimidine (23 g)was suspended under ice cooling in 250 ml of phosphorus oxychloride, 14ml of N,N-dimethylaniline was added dropwise to this suspension over aperiod of five minutes under ice cooling, the mixture was stirred atroom temperature for ten minutes and then refluxed for five hours. Afterremoving excess phosphorus oxychloride by distillation from the reddishbrown solution under normal pressure, about 50 ml of a reddish brown oilwas obtained. It was shaken with 300 ml of dichloromethane and 200 ml ofwater, the organic layer was collected, and the red aqueous layer wasextracted with 200 ml of dichloromethane. The organic layers were joinedtogether, washed with saturated sodium bicarbonate solution until the pHof the washings rose to 7-8, then with 100 ml of saturated sodiumchloride solution. After drying over anhydrous magnesium sulfate, thered solution was concentrated to about 30 ml, and 30 ml of n-hexane wasadded to the concentrate for recrystallization, affording 18 g of theobjective compound as faint yellow crystals.

(Step 2)

Preparation of 2-carboxy-7-mercapto-5-methyl-s-triazolo[1,5-a]pyrimidine.

The product obtained in Step 1 (17 g) was added at a time, in a nitrogenatmosphere, to a solution of sodium hydrosulfide (16 g) in 280 ml ofwater at room temperature with stirring, and the mixture was heated to60° C. with stirring continued. The resultant yellow solution was cooledto room temperature, the insoluble matters were filtered off, thefiltrate was acidified with concentrated hydrochloric acid to pH 2.0,and the crystals thus formed were collected by filtration and washedtwice with 20 ml of water, affording 10 g of the objective compound asyellow crystals. M.P.: 215.4°-217.3° C.

EXAMPLE 2

Preparation of 6-carboxy-7-mercapto-s-triazolo-[1,5-a]pyrimidine

(Step 1)

Preparation of 7-chloro-6-ethoxycarbonyl-s-triazolo [1,5-a]pyrimidine

A suspension of 6-ethoxycarbonyl-7-hydroxy-s-triazolo [1,5-a]pyrimidine(7 g) in phosphorus oxychloride (20 ml) was refluxed for 30 minutes, theresultant orange solution was further refluxed for one hour, and excessphosphorus oxychloride was removed by distillation under reducedpressure. Benzene (50 ml) was added to the residue, and remainingphosphorus oxychloride was completely removed by azeotropic distillationunder reduced pressure. Chloroform (80 ml) was added to the residue, theinsoluble matters were filtered off, and the solvent was removed invacuo from the filtrate. Purification of the brown residue by silica gelcolumn chromatography gave 3.9 g of the objective compound as colorlesscrystals.

M.P.: 130.0°-132.0° C.

NMR (DMSO-d₆, δ):

9.3 (1H, s), 8.6 (lH, s), 4.5 (2H, q), 1.5 (3H, t).

(Step 2)

Preparation of 6-ethoxycarbonyl-7-mercapto-s-triazolo [l,5-a]pyrimidine

The product obtained in Step 1 (3.6 g) and sodium hydrosulfide (2.5 g)were dissolved in 50 ml of water, the solution was stirred at roomtemperature for 20 minutes, its pH was lowered to 1.0 with 6Nhydrochloric acid, and the crystals thus formed were collected byfiltration, affording 3.0 g of the objective compound as yellowcrystals.

NMR (DMSO-d₆, δ):

8.7 (1H, s), 8.4 (1H, s), 4.3 (2H, q), 1.3 (3H, t).

(Step 3)

Preparation of 6-carboxy-7-mercapto-s-triazolo[1,5-a]pyrimidine

The product obtained in Step 2 (2.4 g) was dissolved in 50 ml of aqueoussolution containing 1.0 g potassium hydroxide, the solution was heatedat 80° C. for one hour, the insoluble matters were filtered off, and theclear, faint yellow filtrate was washed with 30 ml ethyl acetate. The pHof the aqueous layer was lowered to 1.0 with concentrated hydrochloricacid, and the crystals thus formed were collected by filtration,affording 2.0 g of the objective compound as colorless crystals.

M.P.: 247.0°-249.0° C.

NMR (DMSO-d₆, δ): 9.0 (1H, s), 8.9 (1H, s).

EXAMPLE 3

Preparation of 2-carboxymethyl-7-mercapto-5-methyl-s-triazolo[1,5-a]pyrimidine

(Step 1)

Preparation of 2-cyanomethyl-5-methyl-7-hydroxy-s-triazolo[1,5-a]pyrimidine,

2-Chloromethyl-5-methyl-7-hydroxy-s-triazolo[1,5-a]pyrimidine (4 g) wasadded to a solution of 2 g of sodium cyanide in 10 ml ofdimethylformamide with stirring, and the mixture was heated at 50° C.for two hours and then at 80° C. for three hours. After cooling, 60 mlof 6N hydrochloric acid was added, the mixture was extracted with 100 mlethyl acetate, the organic layer was concentrated under reducedpressure, and the crystals thus formed were collected and washed with anethyl acetate/ether mixed solvent, affording 2.4 g of the objectivecompound.

M.P 277.5°-278.5° C.

(Step 2)

Preparation of 2-carboxymethyl-7-hydroxy-5-methyl-s-triazolo[1,5-a]pyrimidine.

The product obtained in Step 1 (2.1 g) was dissolved in 10 ml ofconcentrated hydrochloric acid, the solution was refluxed for 20minutes, 200 ml of water was added, and the crystals thus separated werecollected by filtration and washed with a methanol/ether mixed solvent,affording 1.5 g of the objective compound.

M.P.: 266.5°-270.0° C.

(Step 3)

Preparation of7-hydroxy-2-methoxycarbonylmethyl-5-methyl-s-triazolo[1,5-a]pyrimidine

A solution of the product obtained in Step 2 (1.5 g) in 50 ml ofmethanol was cooled to 0° C., 24 ml of thionyl chloride was addeddropwise to this solution at that temperature, and the mixture wasrefluxed for 1.5 hours. After removing the solvent by distillation underreduced pressure, the residue was recrystallized from ethylacetate/ether, giving 1.5 g of the objective compounds.

M.P.: 224.5°-226.5° C.

(Step 4)

Preparation of7-chloro-2-methoxycarbonylmethyl-5-methyl-s-triazolo[1,5-a]pyrimidine

A solution of the product obtained in Step 3 (1.5 g) in 15 ml ofphosphorus oxychloride was refluxed for two hours, excess phosphorusoxychloride was distilled off, the residue was dissolved in chloroform,and the solution was washed with ice water. After removing the solventfrom the organic layer under reduced pressure, the residue was purifiedby silica gel chromatography, affording 1 g of the objective compound.

M.P.: 111.0°-111.5° C.

(Step 5)

Preparation of7-mercapto-2-methoxycarbonylmethyl-5-methyl-s-triazolo[1,5-a]pyrimidine

The product obtained in Step 4 (2 g) and sodium hydrosulfide (1.22 g)were dissolved in 35 ml of water, the solution was stirred at roomtemperature for 1.5 hours under a nitrogen stream, and the insolublematters were filtered off. The filtrate was cooled to 0° C., its pH waslowered to 1-2 with 6N hydrochloric acid, the slurry was stirred at thattemperature for 30 minutes, and the crystals thus formed were collectedby filtration, washed with 30 ml of water and dried, affording 1.44 g ofthe objective compound.

M.P.: 213.0°-214.0° C.

(Step 6)

Preparation of2-carboxymethyl-7-mercapto-5-methyl-s-triazolo[1,5-a]pyrimidine

The product obtained in Step 5 (1.5 g) was added to a solution of 0.75 gpotassium hydroxide in 10 ml of water, the mixture was stirred at roomtemperature for two hours, and its pH was lowered to 1-2 with 6Nhydrochloric acid. The crystals thus formed were collected byfiltration, washed with 50 ml of water and dried, giving 1.3 g of theobjective compound.

M.P.: 253.0°-255.0° C.

EXAMPLE 4

Preparation of 5-carboxymethyl-7-mercapto-s-triazolo[1,5-a]pyrimidine

(Step 1)

Preparation of5-ethoxycarbonylmethyl-7-hydroxy-s-triazolo[1,5-a]pyrimidine

A suspension of 3-amino-s-triazole (28 g) and diethylacetonedicarboxylate (100 g) in 100 ml of acetic acid was refluxed forsix hours. After cooling to room temperature, 150 ml of concentratedhydrochloric acid was added under ice cooling, the crystals thus formedwere collected by filtration, and washed twice with 100 ml of ethanol,then once with 100 ml of ether, affording 71 g of the objective compoundas colorless crystals.

NMR (DMSO-d₆,δ)

13.2 (1H, s), 8.3 (1H, s), 6.0 (1H, s), 4.2 (2H, q), 3.9 (2H, s), 1.2(3H, t).

(Step 2)

Preparation of7-chloro-5-ethoxycarbonylmethyl-s-triazolo[1,5-a]pyrimidine

The product obtained in Step 1 (30 g) was suspended in 300 ml ofphosphorus oxychloride, 19 ml of N,N-dimethylaniline was added dropwiseto this suspension over a period of five minutes, and the mixture washeated at 50° C. for three hours. Excess phosphorus oxychloride wasremoved from the reddish brown solution under reduced pressure and about70 ml of a reddish brown oil was obtained. It was dissolved in 200 ml ofdichloromethane, and saturated sodium bicarbonate solution was added tothis solution under ice cooling to adjust the pH to 7.5. The reddishbrown aqueous layer was separated, extracted thrice with 100 ml ofdichloromethane, the extract was joined with the dichloromethanesolution separated above, the combined organic solution was washed with10 ml of saturated sodium chloride solution, and dried over anhydrousmagnesium sulfate. The dried filtrate was concentrated to about 40 mlunder reduced pressure, affording 25 g of the objective compound asyellow oil.

NMR (DMSO-d₆,δ):

8.5 (1H, s), 7.4 (1H, s), 4.2 (2H, q), 4.0 (2H, s), 1.3 (3H, q).

(Step 3)

Preparation of5-ethoxycarbonylmethyl-7-mercapto-s-triazolo[1,5-a]pyrimidine

The product obtained in Step 2 (24 g) was added all at once, under anitrogen stream, to a solution of 23 g sodium hydrosulfide in 600 ml ofwater, the mixture was stirred at room temperature for two hours, andthe insoluble matters were filtered off. The filtrate was acidified topH 2.0 with concentrated hydrochloric acid, and the crystals thus formedwere collected by filtration, washed twice with 40 ml of water anddried, affording 22 g of the objective compound as yellow crystals.

NMR (DMSO-d₆,δ):

12.9 (1H, bs), 8.8 (1H, s), 7.1 (1H, s), 4.1 (2H, q), 3.8 (2H, s), 1.2(3H, t).

(Step 4)

Preparation of 5-carboxymethyl-7-mercapto-s-triazolo[1,5-a]pyrimidine

The product obtained in Step 3 (20 g) was added to a solution of 10 g ofpotassium hydroxide in 200 ml of water, the mixture was heated at 60° C.for two hours. After cooling the resulting yellow solution, its pH waslowered to 2.0,with concentrated hydrochloric acid, and the yellowcrystals thus formed were collected by filtration, washed twice with 30ml of water and dried, giving 13 g of the objective compound as yellowcrystals. M.P.: 283.0°-286° C.

EXAMPLE 5

Preparation of 5-carboxy-7-mercapto-s-triazolo[1,5-a]pyrimidine

(Step 1)

Preparation of 7-chloro-5-ethoxycarbonyl-s-triazolo[1,5-a]pyrimidine

A suspension of 5-ethoxycarbonyl-7-hydroxy-s-triazolo[1,5-a]pyrimidine(6.8 g) in 40 ml of phosphorus oxychloride was heated at 60° C. withstirring, the resultant clear, orange solution was further refluxed forone hour, excess phosphorus oxychloride was distilled off, the brownresidue was dissolved in 100 ml of chloroform, and the solution wasslowly added to 100 ml of water with stirring. The chloroform solutionwas separated, dried over anhydrous sodium sulfate, the solvent wasremoved by distillation under reduced pressure, and the residue waspurified by silica gel chromatography, affording 4.6 g of the objectivecompound as colorless crystals.

M.P.: 92.5°-94.0° C.

NMR (DMSO-d₆,δ):

8.8 (1H, s), 7.9 (1H, s), 4.5 (2H, q), 1.4 (3H, t).

(Step 2)

Preparation of 5-ethoxycarbonyl-7-mercapto-s-triazolo[1,5-a]pyrimidine

The product obtained in Step 1 (4.1 g) and sodium hydrosulfide (2.6 g)were dissolved in 30 ml of water, the solution was refluxed for onehour, the reaction mixture was cooled to room temperature, its pH waslowered to 1.0 with 6N hydrochloric acid, and the colorless crystalsthus formed were collected by filtration, giving 2.8 g of the objectivecompound.

M.P : 187.5°-189.0° C.

NMR (DMSO-d₆,δ):

8.3 (1H, s), 7.1 (1H, s), 4.4 (2H, q), 1.4 (3H, t)

(Step 3)

Preparation of 5-carboxy-7-mercapto-s-triazolo[1,5-a]pyrimidine

The product obtained in Step 2 (2.0 g) was dissolved in a solution of1.0 g potassium hydroxide in 80 ml of water, the mixture was heated at80° C. for 30 minutes. After cooling the resulting orange solution toroom temperature, it was washed with 50 ml of ethyl acetate, the pH ofthe aqueous layer was lowered to 1.0 with 6N hydrochloric acid, and thecrystals thus formed were collected by filtration, washed with 50 ml ofacetone, giving 1.6 g of the objective compound as orange crystals.

M.P.: 230.5°-232.0° C.

NMR (DMSO-d₆,δ):

8.3 (1H, s), 7.1 (1H, s)

EXAMPLE 6

Preparation of 2,6-dicarboxy-7-mercapto-s-triazolo[1,5-a]pyrimidine

(Step 1)

Preparation of6-ethoxycarbonyl-7-hydroxy-2-methoxycarbonyl-s-triazolo[1,5-a]pyrimidine

A mixture of methyl 3-amino-s-triazolocarboxylate (18 g), diethylethoxymethylenemalonate (27 g) and 50 ml of acetic acid was refluxed forthree hours. The crystals formed upon cooling with ice were collected byfiltration, and recrystallized from 50 ml of acetic acid, affording 40 gof the objective compound as colorless crystals.

NMR (DMSO-d₆,δ):

8.2 (1H, s), 4.3 (2H, q), 3.9 (3H, s), 1.3 (3H, t).

(Step 2)

Preparation of7-chloro-6-ethoxycarbonyl-2-methoxycarbonyl-s-triazolo[1,5-a]pyrimidine

The product obtained in Step 1 (12 g) was suspended in 100 ml ofphosphorus oxychloride, 5.9 g of N,N-dimethylaniline was added dropwiseto this suspension at 0° C. with stirring over a period of ten minutes,and the mixture was stirred at room temperature for 30 minutes and thenrefluxed for four hours. Removing excess phosphorus oxychloride bydistillation under normal pressure gave about 50 ml of a reddish brownoil. It was dissolved in 300 ml of dichloromethane, the solution waswashed with 500 ml of saturated sodium bicarbonate solution, then with80 ml of saturated sodium chloride solution, and the organic layer wasdried over anhydrous magnesium sulfate. The dried reddish yellowfiltrate was concentrated to about 30 ml, and crystallized from 20 ml ofn-hexane, affording 8.5 g of the objective compound as faint yellowcrystals.

M.P.: 149.0°-151.8° C.

NMR (DMSO-d₆,δ):

8.7 (1H, s), 4.3 (2H, q), 3.4 (3H, s), 1.3 (3H, t).

(Step 3)

Preparation of 2,6-dicarboxy-7-mercapto-s-triazolo[1,5-a]pyrimidine

The product obtained in Step 2 was added at a all at once, under anitrogen stream, to a solution of 5 g of sodium hydrosulfide in 150 mlof water, the mixture was stirred at room temperature for three hours,and 4 g of potassium hydroxide was added to the yellow slurry. Thismixture was heated at 60° C. for three hours, and the insoluble matterswere filtered off after cooling to room temperature. The orange filtratewas acidified to pH 2.0 with concentrated hydrochloric acid, thecrystals thus formed were collected by filtration, washed twice with 10ml of water and dried, affording 4.0 g of the objective compound asyellow crystals.

M.P.: 292.4°-294.8° C. (dec)

EXAMPLE 7

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid (Compound 2)

(Step 1)

Preparation of(6R,7R)-3-acetoxymethyl-7-[2-(2-chloroacetamido-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

Triethylamine (14 ml) was added to a solution of 23 g of2-(2-chloroacetamido-4-thiazolyl)-2-(Z-methoxyimino)acetic acid in 100ml of dichloromethane, and 17.3 g of phosphorus pentachloride was thenadded dropwise at 0° C. over a period of ten minutes. After stirring themixture at 0° C. for ten minutes and then at room temperature for onehour, dichloromethane was removed by distillation under reducedpressure, the residue was washed twice with 30 ml of n-hexane to removeexcess phosphorus pentachloride, the brown solid left was dissolved in100 ml of tetrahydrofuran, and the phosphorus pentachloride still leftwas removed by filtration. This acid chloride solution intetrahydrofuran was added dropwise under ice cooling over a period of 20minutes to an ice-cooled solution of 20.3 g of 7-aminocephalosporanicacid and 19 g of bis(trimethylsilyl)acetamide in 150 ml of drydichloromethane, and the mixture was stirred at room temperature for twohours. After removing the solvent by distillation under reducedpressure, the brown residue was added to a mixture of 250 ml of ethylacetate and 80 ml of water, and the pH was adjusted to 7.5 with sodiumbicarbonate, followed by washing with ethyl acetate. The aqueous layerwas collected, its pH was lowered to 2.0 with 1N hydrochloric acid, thecrystals thus formed were collected by filtration, washed twice with 50ml of water and then once with 50 ml of 50% aqueous acetone, andthoroughly dried, giving 32 g of the objective compound as colorlesscrystals.

IR (KBr, cm-1):

1780, 1550, 1235, 1040.

NMR (DMSO-d₆,δ):

9.5 (1H, d, 8 Hz), 8.1 (1H, s), 6.8 (1H, s), 4.7 (2H, s), 3.9 (3H, s),2.0 (3H, s).

(Step 2)

Preparation of(6R,7R)-3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

The product obtained in Step 1 (10.2 g) was dissolved in 80 ml ofdimethylacetamide, 2.8 g of thiourea was added to this solution at roomtemperature in small portions over a period of ten minutes, and themixture was stirred at room temperature for an additional three hours.After concentration of the reaction mixture under reduced pressure, 200ml of ethyl acetate and 80 ml of water were added to the brown residue,the pH was adjusted to 7.8 with sodium bicarbonate, and the aqueouslayer was washed with ethyl acetate until no thiourea could be detectedin the aqueous layer. The pH of aqueous layer was lowered to 2.0, thecrystals thus formed were collected by filtration, washed twice with 30ml of water and then once with 10 ml of 50% aqueous acetone, and dried,giving 5.5 g of the objective compound as colorless crystals.

IR (KBr, cm-1):

1770, 1735, 1530, 1240, 1040.

NMR (DMSO-d₆,δ):

9.5 (1H, d, 7 Hz), 6.7 (1H, s), 3.8 (3H, s), 2.0 (3H, s).

(Step 3)

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylicacid

A suspension of the product obtained in Example 1 (2.1 g) and sodiumbicarbonate (2.5 g) in 100 ml of 0.1 M phosphate buffer (pH 6.4) washeated with stirring, and the product obtained in Step 2 (4.6 g) wasadded to this suspension over a period of 20 minutes. The mixture wasthen heated to 60° C., and stirred at this temperature for five hourswhile maintaining the pH between 6.8 and 7.2. At the end of reaction,the resulting solution was allowed to cool to room temperature, washedtwice with 100 ml of ethyl acetate, and the pH of the brown aqueouslayer was lowered to 2.0 with 1N hydrochloric acid. The formed crystalswere collected by filtration, washed twice with 30 ml of water, thenonce with 15 ml of 50% aqueous acetone, giving the objective compound ascolorless crystals.

IR (KBr, cm-1): 1770, 1625, 1510, 1040.

NMR (DMSO-d₆,δ):

9.6 (1H, d, 8 Hz), 7.4 (1H, s), 6.7 (1H, s), 5.8 (1H, dd, 8 Hz, 5 Hz),5.2 (1H, d, 5 Hz), 4.5 (2H, ABq), 3.8 (3H, s), 3.7 (2H, ABq), 2.6 (3H,s).

EXAMPLE 8

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia--azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (Compound 1)

(Step 1)

Preparation of(6R,7R)-7-amino-3-[(5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

A suspension of 7-mercapto-5-methyl-s-triazolo[1,5-a]pyrimidine (6 g)and sodium bicarbonate (6.2 g) in 130 ml of 0.1M phosphate buffer (pH6.4) was heated at 40° C. with stirring, 7-aminocephalosporanic acid (10g) was added to this hot solution over a period of 30 minutes, and thesuspension was heated to 60° C. with continued stirring. The pH of theresulting clear, brown solution was adjusted to 6.8-7.2, and heating wascontinued for an additional six hours. After allowing it to cool to roomtemperature, the brown solution was washed twice with 100 ml of ethylacetate, the aqueous layer was separated, and its pH was adjusted to 2.0with 1N hydrochloric acid. The formed crystals were collected byfiltration, washed twice with 50 ml of water, and dissolved in 80 ml ofacetonitrile by heating to 35° C. After adding 2 g of activatedcharcoal, the hot solution was allowed to stand for one hour, thecharcoal was filtered off, and the filtrate was concentrated to about 20ml at a temperature below 30° C. The formed colorless crystals werecollected by filtration, giving 9.8 g of the objective compound.

IR (KBr, cm-1): 1795, 1520, 1410, 1350.

NMR (DMSO-d₆,δ):

8.7 (1H, s), 7.4 (1H, s), 2.6 (3H, s).

(Step 2)

Preparation of(6R,7R)-7-[2-(2-chloroacetamido-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

Using 2-(2-chloroacetamido-4-thiazolyl)-2-(Z-methoxyimino)acetic acid(6.6 g), triethylamine (4.2 ml,, phosphorus pentachloride (5.5 g),dichloromethane (40 ml), n-hexane (60 ml) and anhydrous tetrahydrofuran(50 ml), a 50ml solution of the corresponding acid chloride was preparedby a method similar to Step 1 of Example 7. This chloride solution wasadded dropwise to a solution of the product obtained in Step 1 (9 g) andbis(trimethylsilyl)acetamide (14 g) in 100 ml anhydrous dichloromethaneat 0° C. with stirring over a period of 20 minutes, and the mixture wasstirred at 0° C. for an additional 20 minutes and then at roomtemperature for two hours. After removing the solvent by distillationunder reduced pressure, the brown residue was shaken with a mixture ofethyl acetate (200 ml) and water (80ml), the pH was adjusted to 7.5 withsodium bicarbonate, and the aqueous layer was then separated and washedwith ethyl acetate. The pH of the aqueous layer was adjusted to 2.0 with1N hydrochloric acid, the formed crystals were collected by filtration,and washed twice with 30 ml of water and then once with 20 ml of 50%aqueous acetone, affording 7.5 g of the objective compound as colorlesscrystals.

IR (KBr, cm-1): 1785, 1690, 1040.

NMR (DMSO-d₆,δ):

9.6 (1H, d), 8.5 (1H, s), 8.0 (1H, s), 7.3 (1H, s), 6.7 (1H, s), 4.4(2H, s), 3.8 (3H, s), 2.6 (3H, s).

(Step 3)

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0.]oct-2-ene-2-carboxylicacid

The product obtained in Step 2 (5 g) was dissolved in 150 mldimethylacetamide, 11.9 g thiourea was added to this solution at roomtemperature with stirring over a period of 20 minutes, and the mixturewas stirred at room temperature for three hours. After removing thesolvent by distillation at a temperature below 20° C. under a pressureof 1 mmHg, the residue was added to a mixture of ethyl acetate (200 ml)and water (80 ml), and the pH was adjusted to 7.8 with sodiumbicarbonate. The aqueous layer was washed with ethyl acetate until nothiourea could be detected. The pH was lowered to 2.0 with 1Nhydrochloric acid, the formed crystals were collected by filtration, andwashed twice with 20 ml of water, then once with 10 ml of 50% aqueousacetone, affording 3 g of the objective compound as colorless crystals.

IR (KBr, cm-1): 1775, 1630, 1520, 1040.

NMR (DMSO-d₆,δ): 9.5 (1H, d, 7 Hz), 8.6 (1H, s), 7.3 (1H, s), 6.7 (1H,s), 3.8 (3H, s), 2.6 (3H, s).

EXAMPLE 9

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(6-carboxy-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid (Compound 3)

A suspension of the product obtained in Example 2 (3 g) and sodiumbicarbonate (4.5 g) in 160 ml of 0.1M phosphate buffer (pH 6.4) washeated to 40° C. with stirring, and the product obtained in Step 2 ofExample 7 (8.8 g) was added to this hot suspension over a period of 20minutes. The mixture was then heated to 60° C., and stirred at thistemperature for six hours while maintaining the pH between 6.8 and 7.2.At the end of reaction, the resulting solution was allowed to cool toroom temperature, was washed with 200 ml of ethyl acetate, and the pH ofthe aqueous layer was adjusted to 2.0 with 1N hydrochloric acid. Theformed crystals were collected by filtration, and washed twice with 50ml of water and then once with 30 ml of 50% aqueous acetone, giving 4.9g of the objective compound as colorless crystals.

IR (KBr, cm-1): 1770, 1530, 1040.

NMR (DMSO-d₆,δ):

9.5 (1H, d, 7 Hz), 9.0 (1H, s), 8.7 (1H, s), 6.8 (1H, s), 3.8 (3H, s).

EXAMPLE 10

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(5-carboxymethyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid (Compound 5)

Starting from the product obtained in Example 4 (2.1 ) and the productobtained in Step 2 of Example 7 (4.6 g), 5 g of the objective compoundwas obtained as colorless crystals in a manner similar to Example 9.

IR (KBr, cm-1): 1770, 1520, 1360, 1040.

NMR (DMSO-d₆,δ):

9.6 (1H, d, 7 Hz), 8.5 (1H, s), 7.2 (1H, s), 6.8 (1H, s), 3.8 (5H, s).

EXAMPLE 11

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(2-carboxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid (Compound 4)

Starting from the product obtained in Example 3 (2.2 g) and the productobtained in Step 2 of Example 7 (4.6 g), 5 g of the objective compoundwas obtained as colorless crystals in a manner similar to Example 9.

IR (KBr, cm-1): 1770, 1520, 1040.

NMR (DMSO-d₆,δ):

9.6 (1H, d, 7 Hz), 7.2 (1H, s), 6.7 (1H, s), 3.8 (5H, s), 2.5 (3H, s).

EXAMPLE 12

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)-acetamido]-3-[(5-carboxy-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid (Compound 6)

Starting from the product obtained in Example 5 (1.6 g) and the productobtained in Step 2 of Example 7 (4.4 g), 3.8 g of the objective compoundwas obtained as colorless crystals in a manner similar to Example 9.

IR (KBr, cm-1): 1770, 1540, 1360, 1190, 1040.

NMR (DMSO-d₆,δ):

9.6 (1H, d, 8 Hz), 8.6 (1H, s), 7.6 (1H, s), 6.8 (1H, s), 3.9 (3H, s).

EXAMPLE 13

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)-acetamido]-3-[(2,6-dicarboxy-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid (Compound 7)

Starting from the product obtained in Example 6 (1.2 g) and the productobtained in Step 2 of Example 7 (2.3 g), 2 g of the objective compoundwas obtained as colorless crystals in a manner similar to Example 9.

IR (KBr, cm-1):

1770, 1630, 1040.

NMR (DMSO-d₆,δ):

9.6 (1H, d, 7 Hz), 9.1 (1H, s), 6.7(1H, s), 3.8 (3H, s).

EXAMPLE 14

Preparation of(6R,7R)-7-amino-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

To a suspension of 7-aminocephalosporanic acid (153 g) and the productobtained in Example 1 (118 g) in 850 ml acetonitrile, was added borontifluoride etherate (240 g) at room temperature over a period ofminutes, and the resultant suspension was heated at 45°-55° C. withstirring. The mixture turned into a dark yellow solution in about 20minutes. After heating at that temperature for two hours, the reactionmixture was cooled on ice, 900 ml of water was added over a period of 10minutes. The solution became gradually turbid, and crystals began toseparate out. Collecting them by filtration, followed by washing thricewith 150 ml of water, then thrice with 200 ml of acetone, 190 g of theobjective compound was obtained as colorless crystals.

IR (KBr, cm⁻¹):

1792, 1610, 1595, 1410, 1240, 1060, 770.

NMR (DMSO-d₆,δ):

7.4 (1H, s), 5.0 (1H, d, 5 Hz), 4.9 (1H, d, 5 Hz), 4.4 (2H, bs), 3.7(2H, ABq), 2.6 (3H, s).

EXAMPLE 15

Preparation of(6R,7R)-7-amino-3-[(2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo[1,5-a]-pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid diphenylmethyl ester

The product obtained in Example 14 (190 g) was suspended in a mixture ofacetone (2 liters) and methanol (300 ml). To this suspension a purplesolution of diphenyldiazomethane (220 g) in 500 ml of dichloromethanewas added dropwise over a period of one hour. The reaction proceededwith effervescence and evolution of heat. After all thediphenyldiazomethane solution was added, the mixture was stirred at roomtemperature for 20 hours, the insoluble matters were filtered off, andthe solvent was removed by distillation from the filtrate under reducedpressure, leaving 380 g of purplish red oil. Ether (800 ml) was added,and the formed crystals were collected by filtration and washed withether, affording 225 g of the objective compound as colorless crystals.

IR (KBr, cm⁻¹):

1795, 1730, 1590, 1510, 1450, 1365, 1295, 1225, 1210, 1170, 1000, 915,765, 700.

NMR (DMSO-d₆,δ):

7.5-7.1 (22H, m), 6.9 (1H, s), 5.0 (1H, d, 5 Hz) 4.9 (1H, d, 5 Hz), 4.3(2H, bs), 3.7 (2H, ABq) 2.6 (3H, s).

EXAMPLE 16

Preparation of(6R,7R)-7-[2-(2-triphenylmethylamino-4-thiazolyl)-2-(Z-1-methoxy-1-methylethyloxyimino)acetamido]-3-[(2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid diphenylmethyl ester.

The product obtained in Example 15 (165 g) and2-(2-triphenylmethylamino-4-thiazolyl)-2-(Z-(1-methoxy-1-methylethyloxyimino)aceticacid (220 g) were dissolved in anhydrous dichloromethane (2.5 liters)with stirring, the faint yellow solution was cooled to -15° C., and asolution of dicyclohexylcarbodiimide (90 g) in anhydrous dichloromethane(500 ml) was added dropwise over a period of 30 minutes. The mixture wasstirred at 0° C. for three hours and then at room temperature for threehours. The insoluble matters were filtered off, and the reddish brownfiltrate was concentrated under reduced pressure, leaving a reddishbrown oil. Ethyl acetate (1 liter) was added, the insoluble matters werefiltered off, and the filtrate was washed with 100 ml of 0.3N aqueouscitric acid, 150 ml of saturated sodium bicarbonate solution andsaturated sodium chloride solution in that order, and dried overanhydrous magnesium sulfate. The dried solution was concentrated invacuo. The brown, viscous oil left (520 g) was purified by silica gelcolumn chromatography using ethyl acetate/n-hexane as eluent, yielding240 g of the objective compound as brown crystals.

IR (KBr, cm⁻¹):

1790, 1735, 1595, 1505, 1445, 1375, 1225, 1205, 1180, 1070, 1000, 950,895, 750, 700.

NMR (DMSO-d₆,δ):

9.5 (1H, d, 8 Hz), 8.8 (1H, s), 7.5-7.2 (37H, m), 7.0 (1H, s), 6.8 (1H,s), 5.9 (1H, dd, 8 Hz, 5 Hz), 5.3 (1H, d, 5 Hz), 4.4 (2H, bs), 3.7 (2H,ABq), 3.1 (3H, s), 2.6 (3H, s), 1.4 (6H, s).

EXAMPLE 17

Preparation of(6R,7R)-7-[2-(2-triphenylmethylamino-4-thiazolyl)-2-(Z-hydroxyimino)acetamido]3-[(2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid diphenylmethyl ester.

To an ice-cooled solution of the product obtained in Example 16 (220 g)in 1.2 liters of acetone was added 250 ml of 1N hydrochloric acid over aperiod of ten minutes, the resulting red solution was stirred at roomtemperature for two hours, and then concentrated to 400-500 ml underreduced pressure at a bath temperature below 20° C. Ethyl acetate (800ml) was added to the concentrate, and the solution was washed with 200ml of saturated sodium chloride solution and dried over anhydrous sodiumsulfate. The dried solution was concentrated in vacuo, and the redviscous product left (190 g) was treated with 500 ml ether, giving 175 gof the objective compound as yellow crystals.

IR (KBr, cm⁻¹):

3380, 2940, 1790, 1735, 1595, 1520, 1505, 1500, 1480, 1225, 1205, 1180,1000, 900, 760, 740, 700.

NMR (DMSO-d₆,δ):

11.3 (1H, s), 9.6 (1H, d, 8 Hz), 8.7 (1H, s), 7.5-7.1 (37H, m), 6.9 (1H,s), 6.6 (1H, s), 5.9 (1H, dd, 8 Hz, 5 Hz), 5.2 (1H, d, 5 Hz), 4.3 (2H,bs), 3.8 (2H, ABq), 2.6 (3H, s).

EXAMPLE 18

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-hydroxyimino)acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid (Compound 8)

The product obtained in Example 17 (2.4 g) was suspended under icecooling in 4 ml anisole, and 40 ml of trifluoroacetic acid containing 2ml of water was added dropwise to this suspension over a period of tenminutes, and the mixture was allowed to stand until room temperature wasreached. After removing the solvent by distillation under reducedpressure, 300 ml ether was added to the residue, and the formed crystalswere collected by filtration and washed with 50% aqueous acetone,affording 0.9 g of the objective compound as light brown crystals.

IR (KBr, cm⁻¹):

1772, 1650, 1600, 1550, 1510, 1410, 1255.

NMR (DMSO-d₆,δ):

11.3 (1H, s), 9.5 (1H, d, 8 Hz), 7.4 (1H, s), 7.1 (2H, s), 6.7 (1H, s),5.8 (1H, dd), 5.2 (1H, d), 4.4 (2H, bs), 3.7 (2H, ABq), 2.6 (3H, s).

EXAMPLE 19

Preparation of(6R,7R)-7-[2-(2-triphenylmethylamino-4-thiazolyl)-2-[Z-(2-furancarbonyl)oxyimino]acetamido]-3-[(2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid diphenylmethyl ester

To an ice-cooled solution of the product obtained in Example 17 (0.5 g)in dry dichloromethane (12 ml) was added potassium carbonate (0.072 g)all at once, followed by dropwise addition of a solution of 2-furoylchloride (0.067 g) in dry dichloromethane (7 ml) over a period of fiveminutes. The mixture was stirred under ice cooling for 40 minutes andthen at room temperature for an additional 40 minutes. After filteringoff the insoluble matters, the filtrate was concentrated under reducedpressure, and the yellow residue was purified by silica gel columnchromatography, giving 0.42 g of the objective compound as faint yellowcrystals.

IR (KBr, cm⁻¹):

1790, 1740, 1690, 1595, 1510, 1470, 1450, 1380, 1290, 1205, 1085, 1060,900, 760, 745, 700.

NMR (DMSO-d₆,δ):

10.1 (1H, d, 8 Hz), 9.2 (1H, s), 8.0 (1H, d, 2 Hz), 7.6-7.2 (39H, m),7.0 (1H, s), 6.7 (1H, dd, 4 Hz, 2 Hz), 6.0 (1H, dd, 8 Hz, 5 Hz), 5.3(1H, d, 5 Hz), 4.4 (2H, bs), 3.8 (2H, ABq), 2.6 (3H, s).

EXAMPLE 20

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-(2-furancarbonyl)oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylicacid (Compound 9)

To an ice-cooled solution of the product obtained in Example 19 (0.4 g)in dichloroethane (2 ml) were added 0.5 ml of anisole and then 0.3 ml oftrifluoroacetic acid. The mixture was stirred at room temperature fortwo hours, the solvent was removed by distillation under reducedpressure, and the residue was crystallized using 10 ml of ether,affording 0.18 g of the objective compound as faint yellow crystals.

IR (KBr, cm⁻¹):

1775, 1735, 1600, 1510, 1470, 1395, 1290, 1070, 775, 750.

NMR (DMSO-d₆,δ):

10.0 (1H, d, 8 Hz), 8.1 (1H, d, 2 Hz), 7.4 (1H, s), 7.4-7.2 (3H, m), 7.1(1H, s), 6.7 (1H, dd, 4 Hz, 2 Hz), 6.0 (1H, dd, 8 Hz, 5 Hz), 5.3 (1H, d,5 Hz), 4.5 (2H, bs), 3.6 (2H, ABq, 18 Hz), 2.6 (3H, s).

EXAMPLE 21

Preparation of(6R,7R)-7-[2-(2-triphenylmethylamino-4-thiazolyl)-2-[Z-(2-thiophenecarbonyl)oxyimino]acetamido]-3-[(2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid diphenylmethyl ester.

Potassium carbonate (219 mg) was suspended in a solution of the productobtained in Example 17 (1.5 g) in dry dichloromethane (36 ml), and theair in the system was replaced with nitrogen. After cooling on icewater, a solution of 2-thiophenecarbonyl chloride (234 mg) in drydichloromethane (20 ml) was added dropwise, the mixture was allowed tostand until room temperature was reached, and dichloromethane (40 ml)was added after two hours. The mixture was washed with water andsaturated sodium chloride solution. The organic layer was dried overanhydrous sodium sulfate, and the solvent was removed by distillationunder reduced pressure. The residue was crystallized from ether, and thecrystals were washed twice with ether, giving 1.4 g of the objectivecompound as faint yellow crystals.

IR (KBr, cm⁻¹):

1792, 1740, 1595, 1510, 1450, 1415, 1250, 1205, 1060, 1010, 740, 700.

NMR (DMSO-d₆,δ):

10.0 (1H, d, 8 Hz), 9.1 (1H, s), 8.0 (2H, m), 7.5-7.0 (40H, m), 6.0 (1H,dd, 8 Hz, 5 Hz), 5.3 (1H, d, 5 Hz), 4.4 (2H, bs), 3.8 (2H, ABq), 2.5(3H, s).

EXAMPLE 22

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-(2-thiophenecarbonyl)oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid (Compound 10)

The product obtained in Example 21 (1.0 g) was dissolved under icecooling in anisole (2 ml), then trifluoroacetic acid (8.8 ml) containing0.8 ml of water was added dropwise to this solution over a period of tenminutes, and the mixture was allowed to stand until room temperature wasreached. After 1.5 hours, the solvent was removed by distillation underreduced pressure. Ether was added to the residue to form crystals. Thecrystals were collected by filtration and washed with dichloromethane,ethyl acetate and ether in that order, affording 590 mg of the objectivecompound as faint yellow crystals.

IR (KBr, cm⁻¹):

1775, 1734, 1600, 1515, 1415, 1250, 1205, 1065, 1015, 740.

NMR (DMSO-d₆, δ):

10.0 (1H, d, 8 Hz), 8.3-7.9 (2H, dd), 7.4 (1H, s), 7.3 (1H, d), 7.1 (1H,s), 6.0 (1H, dd, 8 Hz, 5 Hz), 5.3 (1H, d, 5 Hz), 4.5 (2H, bs), 3.7 (2H,ABq), 2.6 (3H, s).

EXAMPLE 23

Preparation of(6R,7R)-7-[2-(2-triphenylmethylamino-4-thiazolyl)-2-[Z-(3-pyridinecarbonyl)oxyimino]acetamido]-3-[(2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid diphenylmethyl ester

Potassium carbonate (180 mg) was added to a solution of the productobtained in Example 17 (1.0 g) in dry dichloromethane (20 ml). Aftercooling on ice water, a solution of 3-pyridinecarbonyl chloride (180 mg)in 5 ml of dry dichloromethane was added dropwise, the mixture wasstirred at room temperature for two hours, and then washed with waterand saturated sodium chloride solution. The organic layer was dried overanhydrous sodium sulfate, the solvent was removed by distillation underreduced pressure, the residue was purified by silica gel columnchromatography, giving 700 mg of the objective compound as faint yellowcrystals.

IR (KBr, cm⁻¹):

1790, 1744, 1595, 1510, 1205, 760, 740, 700.

NMR (DMSO-d₆,δ):

10.7 (1H, d,), 9.1 (2H, m), 8.8 (1H, dd), 8.3 (1H, dd), 7.7-6.8 (40H,m), 5.8 (1H, dd,), 5.2 (1H, d,), 4.3 (2H, bs), 3.6 (2H, ABq), 2.5 (3H,s).

EXAMPLE 24

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-(3-pyridinecarbonyl)oxyimino]acetamido]3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid (Compound 11)

The product obtained in Example 23 (500 mg) was dissolved indichloroethane (2 ml), then anisole (0.7 ml) and trifluoroacetic acid(1.7 ml) were dropwise added to this solution under ice cooling, and themixture was allowed to stand. After one hour, the reaction mixture waspoured into ether, and the formed crystals were collected by filtrationand washed with ether, affording 200 mg of the objective compound asfaint yellow crystals.

IR (KBr, cm⁻¹): 1773, 1675, 1595, 1510, 1270.

NMR (DMSO-d₆, δ):

10.1 (1H, d, 9 Hz), 9.1 (1H, d), 8.8 (1H, d), 8.3 (1H, d), 7.6 (1H, dd),7.4 (1H, s), 7.1 (1H, s), 6.0 (1H, dd, 9 Hz, 5 Hz), 5.2 (1H, d, 5 Hz),4.4 (2H, bs), 3.7 (2H, ABq, 18 Hz), 2.6 (3H, s).

EXAMPLE 25

Preparation of(6R,7R)-7-[2-(2-triphenylmethylamino-4-thiazolyl)-2-[Z-(3,4-methylenedioxybenzoyl)oxyimino]acetamido]-3-[(2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid diphenylmethyl ester.

Potassium carbonate was added to a solution of the product obtained inExample 17 (2 g) in 30 ml dichloromethane. After cooling with ice water,a solution of 3,4-methylenedioxybenzoyl chloride (520 mg) in 10 ml ofdichloromethane was added dropwise over a period of ten minutes. Themixture was stirred under ice cooling for 45 minutes, then at roomtemperature for one hour, and mixed with 40 ml of dichloromethane. Themixture was washed with 10 ml of water and 20 ml of saturated sodiumchloride solution. The organic layer was dried over anhydrous sodiumsulfate, and the solvent was removed by distillation under reducedpressure. The residue (2.3 g) was purified by silica gel columnchromatography using ethyl acetate/n-hexane as eluent, giving 2.1 g ofthe objective compound as faint yellow crystals.

IR (KBr, cm⁻¹):

1791, 1745, 1600, 1505, 1440, 1260, 1030, 750, 700.

NMR (DMSO-d₆, δ):

9.9 (1H, d, 8 Hz), 9.1 (1H, s), 7.5-7.0 (42H, m), 6.1 (2H, s,), 5.9 (1H,dd, 8 Hz, 5 Hz), 5.2 (1H, d, 5 Hz), 4.4 (2H, bs), 3.8 (2H, bs), 2.5 (3H,s).

EXAMPLE 26

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-(3,4-methylenedioxybenzoyl)oxyimino)]-acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid (Compound 12)

The product obtained in Example 25 (2.1 g) was dissolved indichloroethane (2 ml), then 12 ml of anisole and 2.4 ml oftrifluoroacetic acid were dropwise added to this solution under icecooling, and the reddish yellow solution was stirred for two hours underice cooling. The trifluoroacetic acid was removed under reducedpressure, and the residue was subjected to azeotropic distillation with5 ml of anhydrous benzene to give a dark red oil (18 ml). The oil wasthen treated with 30 ml of ether, and faint yellow crystals (1 g) wereobtained. The crystals were purified by silica gel column chromatographyusing ether containing 1% methanol as eluent, affording 0.7 g of theobjective compound as colorless crystals.

IR (KBr, cm⁻¹):

3400, 1774, 1739, 1580, 1500, 1250, 1030, 730.

NMR (DMSO-d₆, δ):

10.1 (1H, d, 8 Hz), 7.6 (1H, d, 9 Hz), 7.4 (1H, s), 7.2 (1H, m), 7.1(1H, s), 7.0 (1H, d, 9 Hz), 6.1 (2H, s), 6.0 (1H, dd, 8 Hz, 5 Hz), 5.2(1H, d, 5 Hz), 4.5 (2H, bs), 3.8 (2H, bs), 2.6 (3H, s).

EXAMPLE 27

Preparation of2-(2-triphenylmethylamino-4-thiazolyl)-2-[Z-(3,4-methylenedioxybenzoyl)oxyimino]aceticacid

Triethylamine (6.7 ml) was added with stirring to an ice-cooledsuspension of 10 g of2-(2-triphenylmethylamino-4-thiazolyl)-2-(Z-hydroxyimino)acetic acid in140 ml of anhydrous dichloromethane. The suspension turned to a clear,faint yellow solution after ten minutes. A solution of3,4-methylenedioxybenzoyl chloride (3.4 g) in 25 ml of dichloromethanewas dropwise added and the mixture was stirred at room temperature forone hour. The insoluble crystals were removed by filtration and thefiltrate was washed twice with 20 ml of 1N hydrochloric acid and 30 mlof saturated sodium chloride solution each, and dried over anhydroussodium sulfate. The dried filtrate was concentrated under reducedpressure, and the viscous brown residue (14.2 g) was purified by silicagel column chromatography using chloroform/methanol (20-10:1) as eluent,affording 2.3 g of the objective compound as light brown crystals.

NMR (DMSO-d₆, δ):

9.0 (1H, s), 7.7-7.2 (l9H, m), 6.2 (2H, s).

EXAMPLE 28

Preparation of(6R,7R)-7-[2-(2-triphenylmethylamino-4-thiazolyl)-2-[Z-(3,4-methylenedioxybenzoyl)oxyimino]acetamido]-3-[(2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid diphenylmethyl ester.

(Step 1)

Preparation of2-[(2-triphenylmethylamino)-4-thiazolyl]-2-[Z-(3,4-methylenedioxybenzoyl)oxyimino]aceticacid chloride

To an ice-cooled solution of the product obtained in Example 27 (2.3 g)in 30 ml of anhydrous tetrahydrofuran was added with stirring 0.55 ml oftriethylamine, followed by addition of 0.83 g of phosphoruspentachloride ten minutes later. The mixture was stirred at roomtemperature for one hour and the solvent was removed from the resultingbrown solution by distillation under reduced pressure. The residue waswashed twice with 30 ml of n-hexane. The washed solid was dissolved in30 ml of anhydrous tetrahydrofuran, and the insoluble matters werefiltered off. The brown solution thus obtained was submitted to the nextstep without further purification.

(Step 2)

Preparation of(6R,7R)-7-[2-(2-triphenylmethylamino-4-thiazolyl)-2-[Z-(3,4-methylenedioxybenzoyl)oxyimino]acetamido]-3-[(2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid diphenylmethyl ester.

Triethylamine (0.55 ml) was added to an ice-cooled suspension of theproduct obtained in Example 15 (3 g) in 20 ml of anhydroustetrahydrofuran with stirring, giving a clear, light brown solution. Tothis solution was dropwise added the tetrahydrofuran solution of theproduct obtained in Step 1, the pH was adjusted to 7.5 to 8.0 withdicyclohexylamine, and the mixture was stirred at room temperature forthree hours. After filtering off the insoluble matters, the filtrate wasconcentrated under reduced pressure, and the spongy residue was purifiedby silica gel column chromatography using chloroform as eluent,affording 0.5 g of the objective compound as brown crystals.

IR (KBr, cm⁻¹):

1791, 1745, 1600, 1505, 1440, 1260, 1030, 750, 700.

NMR (DMSO-d₆,δ):

9.9 (1H, d, 8 Hz), 9.1 (1H, s), 7.5-7.0 (42H, m), 6.1 (2H, s), 5.9 (1H,dd, 8 Hz, 5 Hz), 5.2 (1H, d, 5 Hz), 4.4-4.3 (2H, bs), 3.8 (2H, s), 2.5(3H, s). The result is in good agreement with that of Example 25.

EXAMPLE 29

Preparation of2-(2-triphenylmethylamino-4-thiazolyl)-2-[Z-(2-furancarbonyl)oxyimino]aceticacid

Triethylamine (8.7 ml) was added to an ice-cooled suspension of2-(2-triphenylmethylamino-4-thiazolyl)-2-(Z-hydroxyimino)acetic2-(Z-hydroxyimino)acetic acid (13 g) in 250 ml of anhydrousdichloromethane with stirring. The suspension turned to a clear, faintyellow solution. A solution of 2-furoyl chloride (3.3 g) in 20 ml ofanhydrous dichloromethane was dropwise added under ice cooling, theresulting light brown solution was stirred at room temperature for onehour, the mixture was poured into 130 ml of ice-cooled 0.5N hydrochloricacid, and the formed crystals were collected by filtration and washedthrice with 30 ml dichloromethane, affording 5.2 g of the objectivecompound as colorless crystals.

IR (KBr, cm⁻¹): 3400, 3000, 1752, 1595, 1576, 1533, 1287, 1065, 701.

NMR (DMSO-d₆, δ): 9.1 (1H, s), 7.7 (1H, d), 7.3 (l5H, s), 7.0 (1H, d),6.9 (1H, s), 6.5 (1H, dd).

EXAMPLE 30

Preparation of(6R,7R)-7-[2-(2-triphenylmethylamino-4-thiazolyl)-2-[Z-(2-furancarbonyl)oxyimino]acetamido]-3-[(2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo[l,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2ene-2-carboxylic acid diphenylmethyl ester.

The product obtained in Example 29 (3.1 g) and the product obtained inExample 15 (4.3 g) were dissolved in anhydrous dichloromethane (200 ml)with stirring, the faint yellow solution was cooled to -30° C., and asolution of dicyclohexylcarbodiimide (1.2 g) in anhydrousdichloromethane (30 ml) was dropwise added over a period of fiveminutes. The resulting faint yellow solution was allowed to stand at 0°C. for nine hours, the colorless crystals separated were removed byfiltration, and the filtrate was washed with 50 ml of 1N aqueous citricacid, 50 ml of saturated sodium bicarbonate solution and 80 ml ofsaturated sodium chloride solution in that order and dried overanhydrous sodium sulfate. The dried filtrate was concentrated in vacuo,the yellow, viscous residue (6.8 g) was purified by silica gel columnchromatography using ethyl acetate/n-hexane as eluent, yielding 5.3 g ofthe objective compound as faint yellow crystals.

IR (KBr, cm⁻¹): 3380, 3050, 3020, 1790, 1740, 1690, 1595, 1510, 1470,1450, 1380, 1290, 1205, 1085, 1060, 900, 760, 745, 700.

NMR (DMSO-d₆, δ): 10.1 (1H, d, 8 Hz), 9.2 (1H, s), 8.0 (1H, d,

2 Hz), 7.6-7.2 (39H, m), 7.0 (1H, s), 6.7 (1H, dd, 2 Hz, 4 Hz), 6.0 (1H,dd, 5 Hz, 8 Hz), 5.3 (1H, d, 5 Hz), 4.4 (2H, bs), 3.8 (2H, ABq ), 2.6(3H, s).

These analytical results are in good agreement with those of Example 19.

EXAMPLE 31

Preparation of(6R,7R)-7-[2-(2-triphenylmethylamino-4-thiazolyl)-2-(Z-cyanomethylthioacetyloxyimino)acetamido]-3-[(2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid diphenylmethyl ester.

To an ice-cooled solution of the product obtained in Example 17 (500 mg)in 15 ml of anhydrous dichloromethane was dropwise added a solution ofcyanomethythioacetyl chloride (77 mg) in 5 ml dichloromethane, and themixture was stirred under ice cooling for 20 minutes. After dilutionwith dichloromethane, the reaction mixture was washed with water andsaturated sodium chloride solution, the organic layer was dried overanhydrous sodium sulfate, the solvent was removed by distillation underreduced pressure, and the residue was treated with ether, affording 510mg of the objective compound as light brown crystals.

IR (KBr, cm³¹ 1):

1785, 1740, 1689, 1595, 1508, 1200, 700.

NMR (DMSO-d₆, δ): 9.9 (1H, d, 8 Hz), 9.0 (1H, s), 7.5-7.1 (38H, m), 7.0(1H, s), 5.8 (1H, dd, 8 Hz, 5 Hz), 5.3 (1H, d, 5 Hz), 4.3 (2H, s), 3.8(2H, s), 3.7 (2H, s), 3.4 (2H, ABq), 2.6 (3H, s).

EXAMPLE 32

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-cyanomethylthioacetyloxyimino)acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid.

The product obtained in Example 31 (500 mg) was dissolved indichloroethane, 0.4 ml of anisole, then 0.9 ml of trifluoroacetic acidwas added dropwise to this solution under ice cooling, and the reactionmixture was stirred at room temperature for 90 minutes. Afterconcentration under reduced pressure, ether was added to the residue,and the formed crystals were collected by filtration and washed withether/chloroform, affording 300 mg of the objective compound as yellowcrystals.

IR (KBr, cm⁻¹): 2245, 1774, 1680, 1595, 1510, 1405, 1245, 1200.

NMR (DMSO-d₆, δ): 10.0 (1H, d), 7.4 (1H, s), 6.7 (1H, s), 5.8 (1H, dd),5.2 (1H, d), 4.4 (2H, bs), 3.7 - 3.4 (6H, m), 2.6 (3H, s).

EXAMPLE 33

Preparation of(6R,7R)-7-[2-(2-triphenylmethylamino-4-thiazolyl)-2-[Z-(thiophene-2-acetyl)oxyimino]acetamido]-3-[(2-diphenylmethyloxycarbonyl5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid diphenylmethyl ester.

Starting from the product obtained in Example 17 (1.0 g) andthiophene-2-acetic acid chloride (138 mg), and using potassium carbonate(146 mg) and dichloromethane (30 ml), 0.87 g of the objective compoundwas obtained as faint yellow crystals in a manner similar to Example 21.

IR (KBr, cm⁻¹): 1790, 1735, 1690, 1475, 1290, 1195, 900, 760, 745,700.

NMR (DMSO-d₆, δ): 9.9 (1H, d, 8 Hz), 9.1 (1H, s), 6.9-7.5 (42H, m), 6.0(1H, dd, 8 Hz, 5 Hz), 5.2 (1H, d, 5 Hz), 4.4 (2H, bs), 4.1 (2H, s), 3.8(2H, ABq), 2.7 (3H, s).

EXAMPLE 34

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-(thiophene-2-acetyl)oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid.

Starting from the product obtained in Example 33 (0.8 g) and usinganisole (1.6 ml) and trifluoroacetic acid (8 ml), 0.4 g of the objectivecompound was obtained as faint yellow crystals in a manner similar toExample 22.

IR (KBr, cm⁻¹): 1790, 1720, 1590, 1510, 1450, 1385, 1300, 1060, 760,745, 700.

NMR (DMSO-d₆, δ): 9.9 (1H, d, 8 Hz), 7.5-6.9 (7H, m), 5.9 (1H, dd, 5 Hz,8 Hz), 5.2 (1H, d, 5 Hz), 4.5 (2H, bs), 4.1 (2H, s), 3.8 (2H, ABq), 2.7(3H, s).

EXAMPLE 35

Preparation of(6R,7R)-7-[2-(2-triphenylmethylamino-4-thiazolyl)-2-[Z-(furan-2-propenoyl)oxyimino)acetamido]acetamido]-3-[(2-diphenylmethyloxycarbonyl5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid diphenylmethyl ester

Starting from the product obtained in Example 17 (1.0 g) andfuran-2-propenoyl chloride (130 mg) and using potassium carbonate (146mg) and dichloromethane (30 ml) , 0.8 g of the objective compound wasobtained as brown crystals in a manner similar to Example 21.

IR (KBr, cm⁻¹): 790, 1730, 1510, 1295, 900, 760, 745, 700.

NMR (DMSO-d₆, δ): 10.0 (1H, d, 8 Hz), 9.3 (1H, s), 7.9 (1H,d, 2 Hz),7.6-7.2 (39H, m), 7.1 (1H, s), 7.0 (1H, d, 4 Hz), 6.7 (1H, dd, 4 Hz, 2Hz), 6.4 (1H, d, 16 Hz), 6.0 (1H, dd, 8 Hz, 5 Hz), 5.3 (1H, d, 5 Hz),4.4 (2H, bs), 3.8 (2H, ABq), 2.6 (3H, s).

EXAMPLE 36

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-(furan-2-propenoyl)oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[l,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid.

Starting from the product obtained in Example 35 (700 mg) and usinganisole (1. ml) and trifluoroacetic acid (7 ml), 0.4 g of the objectivecompound was obtained as light brown crystals in a manner similar toExample 22.

IR (KBr, cm⁻¹): 1775, 1720, 1600, 1390, 1290, 1070, 775, 750.

NMR (DMSO-d₆, δ): 9.9 (1H, d, 8 Hz), 7.9 (1H, d, 2 Hz), 7.6 (1H, d, 16Hz), 7.4 (1H, s), 7.3 (2H, bs), 7.1 (1H, s), 7.0 (1H, d, 4 Hz), 6.7 (1H,dd, 4 Hz, 2 Hz), 6.4 (1H, d,l6 Hz), 5.9 (1H, dd, 8 Hz, 5 Hz), 5.2 (1H,d, 5 Hz), 4.5 (2H, bs), 3.6 (2H, ABq), 2.7 (3H, s).

EXAMPLE 37

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(2-carboxy-5-isopropyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxlicacid

(Step 1)

Preparation of 7-hydroxy-5-isopropyl-2-methoxycarbonyl-s-triazolo[1,5-a]pyrimidine

A mixture of 3-amino-5-methoxycarbonyl-s-triazole (60 g) and ethyl3-oxo-4-methylvalerate (65 g) in 600 ml of acetic acid was refluxed forfive hours, the reaction mixture was cooled to room temperature, its pHwas lowered to 1 to 2 with concentrated hydrochloric acid, and theseparated crystals were recrystallized from ethanol, affording 54 g ofthe objective compound as colorless crystals.

M.P.: 198.2°-200.7° C.

(Step 2)

Preparation of7-choro-5-isopropyl-2-methoxycarbonyl-s-triazolo[1,5-a]pyrimidine

To a suspension of the product obtained in Step 1 (50 g) in 700 ml ofphosphorus oxychloride 31 g of N,N-dimethylaniline was dropwise added atroom temperature over a period of 20 minutes. The mixture was refluxedfor one hour, excess phosphorus oxychloride was removed by distillationunder normal pressure, and the reddish brown residue was dissolved in 2liters of chloroform. This solution was slowly poured into 1.5 liters ofice-cooled saturated sodium bicarbonate solution, the chloroform layerwas collected after shaking, and the aqueous layer was again extractedwith fresh chloroform. The organic layers were joined together, washedwith 800 ml of saturated sodium chloride solution and dried overanhydrous magnesium sulfate. The dried solution was concentrated underreduced pressure to about 100 ml, and 200 ml n-hexane was added to thisconcentrate, giving 47 g of the objective compound as colorlesscrystals.

(Step 3)

Preparation of5-isopropyl-7-mercapto-2-methoxycarbonyl-s-triazolo[1,5-a]pyrimidine

The product obtained in Step 2 (40 g) was added at 0° C. to a solutionof sodium hydrosulfide (40 g) in one liter of water with stiring under anitrogen stream. The mixture was stirred at 0° C. for one hour, then atroom temperature for three hours, and the resulting yellow solution waswashed with 200 ml of ethyl acetate. The aqueous layer was acidifiedwith concentrated hydrochloric acid to pH 2.0, and the formed crystalswere collected by filtration and washed with 100 ml of ethanol,affording 36 g of the objective compound as faint yellow crystals.

M.P.: 179.5°-181.4° C.

(Step 4)

Preparation of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(2-carboxy-5-isopropyl-s-triazolo[l,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid.

Sodium bicarbonate (6.9 g) and the product obtained in Step 3 (10 g)were dissolved in 290 ml of 0.1M phosphate buffer (pH 6.4) at roomtemperature. To this solution 19 g of the product obtained in Step 2 ofExample 7 was added to 40° C. over a period of 20 minutes. The mixturewas then stirred at 60° C. for six hours while maintaining the pHbetween 6.8 and 7.2. After cooling to room temperature, the reactionmixture was washed with 80 ml of ethyl acetate, the aqueous layer wasacidified with 1N hydrochloric acid to pH 2.0, and the formed crystalswere collected by filtration and washed with 30 ml of 50% aqueousacetone, affording 14 g of the objective compound as faint yellowcrystals.

IR (KBr, cm⁻¹): 1765, 1040.

NMR (DMSO-d₆, δ): 9.6 (1H, d, 8 Hz), 7.6 (1H, s), 7.2 (2H, bs), 6.6 (1H,s), 5.7 (1H, dd, 8 Hz, 5 Hz), 5.1 (1H, d, 5 Hz), 4.5 (2H, bs), 3.8 (3H,s), 3.6 (3H, m), 1.3 (6H, d, 7 Hz).

EXAMPLE 38

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(2-carboxy-s-tiazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid(Compound 14)

(Step 1)

Preparation of 7-hydroxy-2-methoxycarbonyl-s-triazolo[1,5-a]pyrimidine

A mixture of 2-amino-5-methoxycarbonyl-s-triazole (50 g) and ethylβ-ethoxyacrylate (75 g) in 500 ml of acetic acid was refluxed for threehours, the reaction mixture was cooled to room temperature, and theformed crystals were collected by filtration and washed with 80 ml ofether, affording 36.5 g of the objective compound as colorless crystals.

(Step 2)

Preparation of 7-chloro-2-methoxycarbonyl-s-triazolo[1,5-a]pyrimidine

To a suspension of the product obtained in Step 1 (35 g) in 400 mlphosphorus oxychloride 24 g of N,N-dimethylaniline was dropwise added atroom temperature. The mixture was refluxed for two hours, excessphosphorus oxychloride was removed by distillation under normalpressure, and the reddish brown oil left was dissolved in 1.5 liters ofchloroform. This solution was slowly poured into 800 ml of ice-cooledsaturated sodium bicarbonate solution, the chloroform layer wascollected after thorough mixing, and the aqueous layer was againextracted with one liter of fresh chloroform. The organic layers werejoined together, washed with 500 ml of saturated sodium chloridesolution, and dried over anhydrous magnesium sulfate. The dried solutionwas concentrated under reduced pressure to about 100 ml, and 200 ml ofn-hexane was added to this concentrate, giving 20 g of the objectivecompound as faint yellow crystals.

(Step 3)

Preparation of 7-mercapto-2-methoxycarbonyl-s-triazolo[1,5-a]pyrimidine

The product obtained in Step 2 was added all at once at 0° C. to asolution of sodium hydrosulfide (20 g) in 450 ml of water with stirringunder a nitrogen stream. The mixture was stirred at 0° C. for one hour,then for two hours at room temperature, and the resulting yellowsolution was washed with 100 ml of ethyl acetate. The aqueous layer wasacidified with concentrated hydrochloric acid to pH 2.0, and the formedcrystals were collected by filtration and washed with 200 ml of ethanol,affording 18 g of the objective compound as faint yellow crystals.

M.P.: 205.8°-206.4° C.

(Step 4)

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(2-carboxy-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

Sodium bicarbonate (7 g) and the product obtained in Step 3 (8.8 g) weredissolved in 300 ml of 0.1M phosphate buffer (pH 6.4) at roomtemperature. To this solution was added the product obtained in Step 2of Example 7 (20 g). The reaction mixture was worked up in the samemanner as Step 4 of Example 37, affording 14 g of the objective compoundas colorless crystals.

IR (KBr, cm⁻¹): 1770, 1045.

NMR (DMSO-d₆, δ): 9.6 (1H, d, 8 Hz), 8.8 (1H, d), 7.5 (1H, d), 7.3 (2H,bs), 6.7 (1H, s), 5.8 (1H, dd, 8 Hz, 5 Hz), 5.2 (1H, d, 5 Hz), 4.4 (2H,bs), 3.8 (3H, s), 3.6 (2H, bs).

EXAMPLE 39

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(2-carboxy5,6-dimethyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

(Step 1)

Preparation of5,6-dimethyl-7-hydroxy-2-methoxycarbonyl-s-triazolo[1,5-a]pyrimidine

A mixture of 3-amino-5-methoxycarbonyl-s-triazole (60 g) and ethyl2-methyl-3-oxo-butylate (93 g) in 300 ml of acetic acid was refluxed forthree hours. The original suspension became clear after heating onehour, and colorless crystals began to form upon further heating. Aftercooling to room temperature, the crystals were collected by filtrationand washed with 300 ml of methanol, affording 55 g of the objectivecompound as colorless crystals.

M.P.: 231°-232.5° C.

(Step 2)

Preparation of7-chloro-5,6-dimethyl-2-methoxycarbonyl-s-triazolo[1,5-a]pyrimidine

To a suspension of the product obtained in Step 1 (50 g) in 500 ml ofphosphorus oxychloride N,N-dimethylaniline (30 g) was dropwise added atroom temperature, the mixture was refluxed for two hours, excessphosphorus oxychloride was removed by distillation under normalpressure, and the black oil left was dissolved in 200 ml of chloroform.This solution was slowly poured into 200 ml of ice-cooled saturatedsodium bicarbonate solution, the chloroform layer was collected afterthorough mixing, and the aqueous layer was again extracted with 200 mlof fresh chloroform. The combined organic layers were washed with 100 mlof saturated sodium chloride solution and dried over anhydrous sodiumsulfate. The dried solution was concentrated under reduced pressure toabout 50 ml, and 100 ml of n-hexane was added to this concentrate,giving 49 g of the objective compound as colorless crystals.

M.P.: 190.5°-192.3° C.

(Step 3)

Preparation of5,6-dimethyl-7-mercapto-2-methoxycarbonyl-s-triazolo[1,5-a]pyrimidine

The product obtained in Step 2 was added all at once at 0° C. to asolution of sodium hydrosulfide (40 g) in 800 ml of water with stirringunder a nitrogen stream, the mixture was stirred at 0° C. for 30 minutesand then at room temperature for 1.5 hours, its pH was lowered to 2.0with concentrated hydrochloric acid. The formed crystals were collectedby filtration and washed with 300 ml of water and 200 ml of ethanol,affording 36 g of the objective compound as yellow crystals.

M.P.: 205.8°-207.1° C.

(Step 4)

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(2-carboxy-5,6-dimethyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

Sodium bicarbonate (7 g) and the product obtained in Step 3 (10 g) weredissolved in 300 ml of 0.1M phosphate buffer (pH 6.4) at roomtemperature. To this solution the product obtained in Step 2 of Example7 (20 g) was added at 40° C. over a period of 30 minutes. The mixturewas stirred at 60° C. for six hours while maintaining the pH between 6.8and 7.2. After cooling to room temperature, the reaction mixture waswashed with 100 ml of ethyl acetate, the aqueous layer was acidifiedwith 1N hydrochloric acid to pH 2.0, and the formed crystals werecollected by filtration and washed with 50 ml of 50% aqueous acetone,affording 15 g of the objective compound as colorless crystals.

IR (KBr, cm⁻¹): 1770, 1640, 1530, 1040.

NMR (DMSO-d₆, δ): 9.6 (1H, d, 8 Hz), 6.7 (1H, s), 3.8 (3H, s), 2.6 (3H,s), 2.5 (3H, s).

EXAMPLE 40

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(5-carboxy-2-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2ene-2-carboxylicacid

(Step 1)

Preparation of5-ethoxycarbonyl-7-hydroxy-3-methyl-s-triazolo[1,5-a]pyrimidine

A mixture of 3-amino-5-methyl-s-triazole (30 g) and diethylacetylenecarboxylate (54 g) in 250 ml ethanol was refluxed for threehours. After cooling to room temperature, the formed crystals werecollected by filtration and washed with methanol, affording 45 g of theobjective compound as faint yellow crystals.

M.P.: 254.6°-256.0° C.

(Step 2)

Preparation of7-chloro-5-ethoxycarbonyl-2-methyl-s-triazolo[1,5-a]pyrimidine

To a suspension of the product obtained in Step 1 (23 g) in 300 ml ofphosphorus oxychloride N,N-dimethylaniline (19 ml) was dropwise added atroom temperature. The mixture was stirred at 80° C. for one hour, excessphosphorus oxychloride was removed by distillation under normalpressure, and the reddish brown oil left was shaken with 500 ml ofchloroform and 200 ml of water. The pH was adjusted to 7 to 8 withsaturated sodium bicarbonate solution, and the chloroform layer wascollected. The aqueous layer was again extracted with 300 ml of freshchloroform. The organic layers were joined together, dried andconcentrated under reduced pressure to about 50 ml, then 100 ml ofn-hexane was added to this concentrate, giving 18 g of the objectivecompound as faint yellow crystals.

M.P.: 133.7°-135.6° C.

(Step 3)

Preparation of 5-ethoxycarbonyl-7-mercapto-2-methyl-s-triazolo[1,5-a]pyrimidine

The product obtained in Step 2 (15 g) was added all at once at roomtemperature to a solution of sodium hydrosulfide (15 g) in 300 ml ofwater with stirring under a nitrogen stream, and the reaction mixturewas worked up in the same manner as Step 3 of Example 37, affording 11 gof the objective compound as yellow crystals.

M.P.: 233.7°-235.8° C.

(Step 4) ps Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(5-carboxy-2-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid Sodium bicarbonate (6.0 g) and the product obtained in Step 3 (8 g)were dissolved in 250 ml of 0.1M phosphate buffer (pH 6.4) at roomtemperature. To this solution the product obtained in Step 2 of Example7 (15 g) was added at 40° C. The reaction mixture was worked up in themanner similar to Step 4 of Example 37, affording 10.5 g of theobjective compound as colorless crystals.

IR (KBr, cm⁻¹): 1770, 1540, 1360, 1190, 1040.

NMR (DMSO-d₆, δ): 9.6 (1H, d, 8 Hz), 8.6 (1H, s), 7.6 (1H, s),6.8 (1H,s), 3.9 (3H, s).

EXAMPLE 41

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(2-hydrazinocarbonyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

(Step 1)

Preparation of2-hydrazinocarbonyl-7-mercapto-5-methyl-s-triazolo[1,5-a]pyrimidine

To a suspension of2-methoxycarbonyl-7-mercapto5-methyl-s-triazolo[1,5-a]pyrimidine (10 g)in 200 ml of methanol was dropwise added hydrazine hydrate (110 ml). Themixture was stirred at room temperature for two hours, the insolublematters were filtered off, and the solvent was removed by distillationfrom the filtrate. Water (100 ml) was added to the residue and the pHwas adjusted to 4.0 with 1N hydrochloric acid. The formed crystals werecollected by filtration and washed with 100 ml of water, then with 100ml of methanol, affording 7.2 g of the objective compound as yellowcrystals.

M.P.: 221.0°-222.2° C.

(Step 2)

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(2-hydrazinocarbonyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

Starting from the product obtained in Step 1 (7 g) and the productobtained in Step 2 of Example 7 (20 g), 11.5 g of the objective compoundwas obtained as colorless crystals in a manner similar to Step 4 ofExample 37.

IR (KBr, cm⁻¹): 1770, 1640, 1530, 1040.

NMR (DMSO-d₆, δ): 9.6 (1H, d, 8 Hz), 6.9 (1H, s), 6.7 (1H,s), 3.8 (3H,s), 2.3 (3H, s).

EXAMPLE 42

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(2-carboxy-5-hydroxy-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid (Compound 15)

(Step 1)

Preparation of5-hydroxy-2-methoxycarbonyl-7-methylthio-s-triazolo[1,5-a]pyrimidine

A suspension of ethyl 2-methylthiocarbonylacetate (37.6 g) an3-amino-5-methoxycarbonyl-s-triazole (20 g) in dimethylformamide (200ml) was refluxed for one hour. After removing the solvent bydistillation under reduced pressure, ether was added to the residue, andthe formed crystals were purified by silica gel chromatography, giving11.7 g of the objective compound.

(Step 2)

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(2-carboxy-5-hydroxy-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

The product obtained in Step 1 (2.1 g) was suspended in 0.1 M phosphatebuffer (75 ml), and sodium bicarbonate (2.65 g) was added to thissuspension to turn it into a solution. The solution was heated to 40°C., the product obtained in Step 2 of Example 7 (5 g) was added, and thereaction mixture was worked up in the manner similar to Step 4 ofExample 37, affording 1.8 g of the objective compound.

IR (KBr, cm⁻¹): 1770, 1640, 1530, 1380, 1040, 750.

NMR (DMSO-d₆, δ): 9.8 (1H, d, 8 Hz), 7.4 (2H, bs), 6.9 (1H, s), 5.9 (1H,dd, 8 Hz, 5 Hz), 5.3 (1H, d, 5 Hz), 3.9 (3H, s).

EXAMPLE 43

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(5-chloro-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

(Step 1)

Preparation of 5-chloro-7-mercapto-s-triazolo[1,5-a]pyrimidine

Thiourea (1.7 g) was added all at once to a solution of 4.2 g of5,7-dichloro-s-triazolo[1,5-a]pyrimidine in 140 ml anhydrous ethanol atroom temperature, the mixture was refluxed for 30 minutes, the crystalsformed upon ice cooling were filtered off, and the filtrate wasconcentrated under reduced pressure. The residue was dissolved in 18 mlof 1N sodium hydroxide solution. The resulting solution was washed with20 ml of ethyl acetate. The pH was adjusted to 1.0 with concentratedhydrochloric acid to give crystals. The crystals were collected byfiltration and washed with 20 ml of water and then with 20 ml ofmethanol, affording 1.2 g of the objective compound as faint yellowcrystals.

M.P.: >300° C.

(Step 2)

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(5-chloro-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

The product obtained in Step 1 (0.33 g) was suspended in 15 ml of 0.1Mphosphate buffer, and 0.53 g of sodium bicarbonate and 1.0 g of theproduct obtained in Step 2 of Example 7 were added. The mixture washeated at 60° C. for five hours while maintaining the pH in the range of6.8 to 7.2, and was worked up in the same manner as Step 4 of Example37, affording 0.36 g of the objective compound.

IR (KBr, cm⁻¹): 1775, 1670, 1630, 1540, 1490, 1185, 1050, 875. NMR(DMSO-d₆, ppm): 9.7 (1H, d, 8 Hz), 8.9 (1H, s), 7.3 (2H, bs), 7.0 (1H,s), 6.8 (1H, s), 5.8 (1H, dd, 8 Hz, 5 Hz), 5.2 (1H, d, 5 Hz), 3.9 (3H,s). Example 44

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(2-amino-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid (Compound 17)

(Step 1)

Preparation of 2-amino-7-chloro-5-methyl -s-triazolo[1,5-a]pyrimidine

2-Amino-7-hydroxy-5-methyl-s-triazolo[1,5-a]pyrimidine (20 g) wassuspended in 120 ml of phosphorus oxychloride under ice cooling, and thesuspension was refluxed for two hours. Excess phosphorus oxychloride wasremoved by distillation under normal pressure. The 40 ml of reddishbrown oil left was shaken with 300 ml of dichloromethane and 200 ml ofwater and the organic layer was collected. The aqueous layer was againextracted with 200 ml of fresh dichloromethane, and the combined organicextract was treated with saturated sodium bicarbonate solution until thepH of washings rose to 7 to 8, then washed with 100 ml of saturatedsodium chloride solution. After drying over anhydrous magnesium sulfate,the dried solution was concentrated under reduced pressure to about 30ml, and the concentrate was crystallized using 80 ml of n-hexane,affording 17 g of the objective compound as faint yellow crystals.

(Step 2)

Preparation of 2-amino-7-mercapto-5-methyl-s-triazolo[1,5-a]pyrimidine

The product obtained in Step 1 (15 g) was added all at once at roomtemperature to a solution of 12 g of sodium hydrosulfide in 300 ml ofwater with stirring under a nitrogen stream. The mixture was stirred atroom temperature for one hour, the insoluble matters were removed byfiltration, the pH was adjusted to 1.0 with concentrated hydrochloricacid, and the formed crystals were collected by filtration and washedtwice with 20 ml water, affording 11 g of the objective compound asyellow crystals. M.P.: >300° C.

(Step 3)

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(2-amino-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

Sodium bicarbonate (8 g) and the product obtained in Stp 2 (6 g) weresuspended in 240 ml of 0.1M phosphate buffer (pH 6.4). To thissuspension the product obtained in Step 2 of Example 7 (15 g) was addedat 40° C. The mixture was heated to 60° C. and the resulting clear,brown solution was stirred at that temperature for six hours whilemaintaining the pH between 6.8 and 7.2. After cooling to roomtemperature, the reaction mixture was washed twice with 100 ml of ethylacetate, the aqueous layer was acidified with 1N hydrochloric acid to pH2.0, and the formed crystals were collected by filtration and washedtwice with 50 ml of 50% aqueous acetone, affording 11 g of the objectivecompound as colorless crystals.

IR (KBr, cm⁻¹): 1770, 1620, 1530, 1040.

NMR (DMSO-d₆, δ): 9.6 (1H, d, 8 Hz), 7.2 (1H, s), 6.7 (1H, s), 3.8 (3H,s), 2.6 (3H, s).

EXAMPLE 45

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)-acetamido]-3-[(2-hydroxysulfonyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid (Compound 18)

(Step 1)

Preparation of 7-hydroxy-5-methyl-s-triazolo[1,5-a]pyrimidine-2-sulfonicacid

To a solution of 5.0 g7-hydroxy-2-mercapto-5-methyl-s-triazolo-[1,5-a]pyrimidine and 2.2 gsodium hydroxide in 40 ml of water was added 63 ml of 30% hydrogenperoxide solution under ice cooling over a period of 15 minutes. Themixture was then heated at 85° C. for four hours with stirring, and thepH was lowered to 1.0 with concentrated hydrochloric acid. Afterconcentrating to about 30 ml under reduced pressure, the separatedcrystals were collected by filtration and washed with 30 ml acetone,affording 5.5 g of the objective compound as colorless crystals.

M.P.: >300° C.

(Step 2)

Preparation of7-chloro-2-chlorosulfonyl-5-methyl-s-triazolo[1,5-a]pyrimidine

To a suspension of the product obtained in Step 1 (10.0 g) in 40 ml ofphosphorus oxychloride was dropwise added 5.5 ml of N,N-dimethylanilineunder ice cooling over a period of 10 minutes. The mixture was stirredat room temperature for ten minutes and then refluxed for one hour.Excess phosphorus oxychloride was distilled away under reduced pressure,and the remaining bluish purple oil was shaken with 200 ml of chloroformand 150 ml of water. The chloroform layer was collected, and the aqueouslayer was again extracted with 200 ml of fresh chloroform. Thechloroform solutions were joined and washed twice with 200 ml ofsaturated sodium bicarbonate solution, once with 100 ml of saturatedsodium chloride solution and dried over anhydrous sodium sulfate. Thechloroform solution was concentrated under reduced pressure to about 20ml, and 50 ml of n-hexane was added to this concentrate to give 6.2 g ofthe objective compound as faint green crystals.

M.P.: 270.0°-275.0° C.

(Step 3)

Preparation of7-chloro-2-ethoxysulfonyl-5-methyl-s-triazolo[1,5-a]pyrimidine

To a suspension of the product obtained in Step 2 (3.5 g) was dropwiseadded 8.6 ml of 1M sodium ethoxide ethanol solution with vigorousstirring under ice cooling over a period of ten minutes. The mixture wasstirred at room temperature for one hour, and the resulting yellowsolution was concentrated under reduced pressure. The remaining yellowoil was shaken with 100 ml of chloroform and 50 ml of water. Thechloroform layer was separated and the aqueous layer was again extractedwith 100 ml of fresh chloroform. The chloroform layers were joined andwashed with 100 ml of saturated sodium chloride solution and dried overanhydrous sodium sulfate. The chloroform solution was concentrated underreduced pressure, and 20 ml of n-hexane was added to the concentrate togive 1.8 g of the objective compound as faint yellow crystals.

M.P.: 166.0°-169.0° C.

(Step 4)

Preparation of7-mercapto-5-methyl-s-triazolo[1,5-a]pyrimidine-2-sulfonic acid

The product obtained in Step 3 (6 g) was added to a solution of 8.1 gsodium hydrosulfide in 100ml of water all at once with stirring under anitrogen at room temperature. The mixture was heated at 60° C. for fourhours with stirring and cooled to room temperature. The resultant yellowsolution was washed twice with 100 ml of ethyl acetate. The pH of theaqueous layer was lowered to 1.0 with concentrated hydrochloric acid forcrystallization. The crystals were collected by filtration and washedwith 20 ml of water; 3.2 g of the objective compound was obtained asyellow crystals.

M.P.: 254.0°-256.0° C.

(Step 5)

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2(Z-methoxyimino)-acetamido]-3-[(2-hydroxysulfonyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

Sodium bicarbonate (0.3 g) and the product obtained in Step 2 of Example7 (0.86 g) were added to a solution of the product obtained in Step 4(0.44 g) in 10 ml of 0.1M phosphate buffer (pH 6.4) and heated at 60° C.for four hours, maintaining the pH in the range of 6.8 to 7.2. Thesolution was then worked up in the same manner as Step 4 of Example 37,affording 0.32 g of the objective compound.

IR (KBr, cm⁻¹): 1775, 1675, 1625, 1590, 1510, 1370, 1330, 1255.

NMR (DMSO-d₆, δ): 9.7 (1H, d, 8 Hz), 7.5 (1H, s), 7.3 (2H, bs) 6.8 (1H,s), 5.9 (1H, dd, 8 Hz, 5 Hz), 5.3

(1H, d, 5 Hz), 4.0 (3H, s), 2.3 (3H, s).

EXAMPLE 46

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(5-methoxy-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid (Compound 16)

(Step 1)

Preparation of 7-mercapto-5-methoxy-s-triazolo[1,5-a]pyrimidine

To a sodium methoxide solution, prepared from 1.4 g of sodium and 50 mlof methanol, was added all at once the product obtained in Step 1 ofExample 43 (4.6 g under ice cooling. The mixture was refluxed for onehour, the solution was concentrated under reduced pressure, and theremaining yellow oil was dissolved in 50 ml water. The pH was adjustedto 1.0 with 1N hydrochloric acid, and the formed crystals were collectedby filtration and washed with 30 ml ethanol, giving 1.7 g of theobjective compound as faint yellow crystals.

M.P.: 182.1°-°183.2° C.

(Step 2)

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(5-methoxy-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

The product obtained in Step 1 (0.3 g) and the product obtained in Step2 of Example 7 (0.95 g) were dissolved in a solution of 0.4 g sodiumbicarbonate in ml of 0.1M phosphate buffer, and the mixture was workedup in the manner similar to Step 4 of Example 37, affording 0.32 g ofthe objective compound.

(KBr, cm⁻¹): 1770, 1660, 1640, 1530, 1385, 1020.

NMR (DMSO-d₆, δ): 9.5 (1H, d, 8 Hz), 8.6 (1H, s), 7.1 (2H, bs), 6.8 (1H,s), 5.6 (1H, dd, 8 Hz, 5 Hz), 5.1 (1H, d, 5 Hz) 3.8 (3H, s), 3.1 (3H,s).

EXAMPLE 47

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(7-hydroxy5-methyl-s-triazolo[1,5-a]pyrimidin-2-yl)thiomethyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid (

Step 1)

Preparation of 7-hydroxy-2-mercapto-5-methyl-s-triazolo[1,5-a]pyrimidine

A mixture of 3-amino-5-mercapto-s-triazole(l0 g), ethyl acetoacetate(34g), piperidine(l0 ml) and ethanol(300 ml) was refluxed for four hours.After removing the solvent by distillation under reduced pressure, 150ml water was added, the mixture was neutralized to pH 7.0 withhydrochloric acid and cooled, giving 5.9 g of the objective compound.

(Step 2)

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(7-hydroxy-5-methyl-s-triazolo[1,5-a]pyrimidin-2-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

Starting from the product obtained in Step 1 (5.5 g) and the productobtained in Step 2 of Example 7 (15 g) and using 7.6 g of sodiumbicarbonate and 240 ml of 0.1M phosphate buffer (pH 6.4), 12.3 g of theobjective compound was obtained in a manner similar to Step 4 of Example37.

IR (KBr, cm⁻¹): 1760, 1680, 1620, 1575, 1513, 1395, 1030.

NMR (DMSO-d₆, δ): 9.6 (1H, d, 8 Hz), 8.3 (1H, s), 7.2 (2H, bs), 6.7 (1H,s), 5.7 (1H, dd, 8 Hz, 5 Hz), 5.1 (1H, d, 5 Hz), 3.8 (3H, s), 2.3 (3H,s)

EXAMPLE 48

Preparation of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-Z-methoxyimino)acetamido]-3-[(6-ethoxycarbonyl-7-hydroxy-s-triazolo[1,5-a]pyrimidin-2-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

(Step 1)

Preparation of6-ethoxycarbonyl-7-hydroxy-2-mercapto-s-triazolo[1,5-a]pyrimidine

A mixture of 15 g 3-amino-5-mercapto-s-triazole, 28 g diethylethoxymethylenemalonate and 70 ml acetic acid was refluxed for 18 hours.After removing the solvent by distillation, the remaining brown oil wasallowed to cool to room temperature, and the pH was adjusted to 10 withsodium hydroxide solution. After washing with 100 ml ethyl acetate, thebrown aqueous solution was neutralized to pH 7.5 with 6N hydrochloricacid, and again washed with 100 ml ethyl acetate. The pH of the aqueouslayer was lowered to 3.0 with 6N hydrochloric acid, and the separatedcrude product (12 g) was collected by filtration and recrystallized from30 ml methanol, giving 9 g of the objective compound as colorlesscrystals.

(Step 2)

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(6-ethoxycarbonyl-7-hydroxy-s-triazolo[1,5-a]pyrimidin-2-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

A solution of the product obtained in Step 1 (4.2 g) and sodiumbicarbonate (4.4 g) in 160 ml of 0.1M phosphate buffer (pH 6.4) washeated at 40° C. with stirring. The product obtained in Step 2 ofExample 7 (10 g) was added over a period of 30 minutes, and theresulting faint yellow solution was heated at 60° C. for two hours whilemaintaining the pH at 6.8 to 7.2. After cooling to room temperature, thebrown solution was washed with 100 ml ethyl acetate, the pH was adjustedto 4.0 with 6N hydrochloric acid, and the aqueous solution was againwashed with 100 ml ethyl acetate. The pH was then lowered to 2.0 with 6Nhydrochloric acid, and the formed crystals were collected and washedwith 10 ml of 50% aqueous acetone, affording 5.2 g of the objectivecompound as brown crystals.

IR (KBr, cm⁻¹): 3300, 1770, 1630, 1590, 1290, 1170, 1040.

NMR (DMSO-d₆, δ): 9.4 (1H, d, 8 Hz), 8.6 (1H, s), 7.2 (1H, bs), 6.7 (1H,s), 5.7 (1H, dd, 8 Hz, 5 Hz), 5.1 (1H, d, 5 Hz), 4.2 (2H, q, 7 Hz), 3.8(3H,s), 1.3 (3H, t, 7 Hz).

EXAMPLE 49

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(6-carboxy7-hydroxy-s-triazolo[1,5-a]pyrimidin-2-yl)thiomethyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid (Compound 19) (

Step 1)

Preparation of6-carboxy-7-hydroxy-2-mercapto-s-triazolo[1,5-a]pyrimidine

The product obtained in Step 1 of Example 48 (2.5 g) was added to asolution of 1.3 g sodium hydroxide dissolved in 20 ml of water andstirred at room temperature for four hours. The pH of the solution wasadjusted to 1-2 with 6N hydrochloric acid. The formed crystals werecollected by filtration, washed with 30 ml of water and dried, affording2.2 g of the objective compound.

(Step 2)

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(6-carboxy-7-hydroxy-s-triazolo[1,5-a]pyrimidin-2-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

A suspension containing the product obtained in Step 1 (1.05 g) andsodium bicarbonate (0.7 g) in 30 ml of 0.1M phosphate buffer (pH 6.4)was heated at 40° C. with stirring. The product obtained in Step 2 ofExample 7 (2.0 g) was slowly added to the suspension and the resultingmixture was stirred at 60° C. for six hours while maintaining the pH inthe range of 6.5 to 7.5. After cooling to room temperature, the reactionmixture was washed with 50 ml of ethyl acetate, the pH was adjusted to2.0 with 1N hydrochloric acid, and the formed crystals were collectedand washed twice with 30 ml of water and once with 30 ml of 50% aqueousacetone, affording 1.2 g of the objective compound. IR (KBr, cm⁻¹):1785, 1720, 1675, 1625, 1540, 1235, 1170, 1040

NMR (DMSO-d₆, δ): 9.6 (1H, d, 8 Hz), 8.6 (1H, s), 6.8

(1H, s), 5.7 (1H, dd, 8 Hz, 5 Hz), 5.2 (1H, d,

5 Hz), 4.3 (2H, m), 3.8 (3H, s), 3.7 (2H, ABq)

EXAMPLE 50

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(7-hydroxy-6-piperidinocarbonyl-s-triazolo[1,5-a]pyrimidin-2-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

(Step 1)

Preparation of7-hydroxy-2-mercapto-6-piperidinocarbonyl-s-triazolo[1,5-a]pyrimidine Toa solution of 7.3 g of 2-amino-5-mercapto-s-triazole and 27.0 g ofdiethyl ethoxymethylenemalonate in 250 ml of ethanol was slowly added8.0 g of piperidine, the mixture was refluxed for seven hours and thenallowed to stand overnight at room temperature. The formed crystals werecollected by filtration and washed with 100 ml of ethanol, affording10.2 g of the objective compound as colorless crystals.

(Step 2)

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(7-hydroxy-6-piperidinocarbonyl-s-triazolo[1,5-a]pyrimidin2-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

A solution of the product obtained in Step 1 (0.58 g) and sodiumbicarbonate (0.44 g) in 15 ml of 0.1M phosphate buffer (pH 6.4) and 5 mlof acetone was heated at 40° C. with stirring. The product obtained inStep 2 of Example 7 (1.0 g) was slowly added, and the resulting solutionwas heated at 60° C. for six hours while maintaining the pH between 6.5and 7.5. After cooling to room temperature, the solution was washed with15 ml of ethyl acetate, the pH was adjusted to 2.0 with 1N hydrochloricacid, and the formed crystals were collected and washed twice with 10 mlof water and once with 10 ml of 50% aqueous acetone, affording 0.65 g ofthe objective compound. IR (KBr, cm⁻¹): 1765, 1610, 1530, 1440, 1035,850, 800.

NMR (DMSO-d₆, δ): 9.6 (1H, d, 8 Hz), 7.4 (1H, s), 7.2 (2H, bs), 5.7 (1H,dd, 8 Hz, 5 Hz), 5.1 (1H, d, 5 Hz), 3.8 (3H, s), 2.3 (3H, s).

EXAMPLE 51

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(7-carboxy-s-triazolo[4,3-a]pyrimidin-5-yl)thiomethyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

(Step 1)

Preparation of 5-chloro-7-ethoxycarbonyl-s-tri

azolo[4,3-a]pyrimidine

7-Ethoxycarbonyl-5-hydroxy-s-triazolo[4,3-a]pyrimidine (10 g) was addedto 50 ml of phosphorus oxychloride at room temperature, the mixture washeated at 60° C. for one hour, and excess phosphorus oxychloride wasremoved by distillation under reduced pressure. The remaining dark redoil was shaken with 200 ml of chloroform and 100 ml of water, and theaqueous layer was again extracted with 100 ml of fresh chloroform. Thechloroform layers were joined together and washed with 80 ml ofsaturated sodium bicarbonate solution and 100 ml of saturated sodiumchloride solution and dried over anhydrous sodium sulfate. The driedsolution was concentrated under reduced pressure to about 50 ml, and theresidue was recrystallized from 100 ml of n-hexane. The crystals werecollected by filtration, affording 6.2 g of the objective compound asfaint yellow crystals.

(Step 2)

Preparation of 7-ethoxycarbonyl-5-mercapto-s-triazolo[4,3-a]pyrimidine

The product obtained in Step 1 (6 g) was added all at once under icecooling to a solution of sodium hydrosulfide (5.5 g) in 100 ml of water,with stirring in nitrogen, and the mixture was stirred at roomtemperature for two hours. After filtering off the insoluble matters,the yellow filtrate was acidified to pH 2.0 with 6N hydrochloric acid,and the formed crystals were collected by filtration, washed with 20 mlof water and air-dried, affording 4.5 g of the objective compound asfaint yellow crystals.

(Step 3)

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(7-carboxy-s-triazolo[4,3-a]pyrimidin-5-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

A solution of the product obtained in Step 2 (3.8 g) and sodiumbicarbonate (4.4 g) in 160 ml of 0.1M phosphate buffer (pH 6.4) washeated at 40° C. with stirring. The product obtained in Step 2 ofExample 7 (10 g) was added over a period of 30 minutes, and the mixturewas heated at 60° C. for five hours while maintaining the pH between 6.8to 7.2. After cooling to room temperature, the brown solution was washedwith 100 ml of ethyl acetate, the pH was adjusted to 4.0 with 6Nhydrochloric acid, and the aqueous solution was again washed with 100 mlof ethyl acetate. The pH was then adjusted to 3.0 with 6N hydrochloricacid, and the formed crystals were collected and washed with 10 ml of50% aqueous acetone, affording 4.3 g of the objective compound as lightbrown crystals.

IR (KBr, cm⁻¹): 3300, 1770, 1610, 1530, 1360, 1035, 740.

NMR (DMSO-d₆, δ): 9.6 (1H, d, 8 Hz), 8.6 (1H, s), 7.4 (1H, s), 7.2 (2H,bs), 6.7 (1H, s), 5.8 (1H, dd, 8 Hz, 5 Hz), 5.2 (1H, d, 5 Hz), 4.5 (2H,bs), 3.7 (2H, bs), 3.8 (3H, s).

EXAMPLE 52

Preparation of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-Z-methoxyimino)acetamido]-3-[(7-carboxy-3-methyl-s-triazolo[4,3-a]pyrimidin-5-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid (Compound 20)

(Step 1)

Preparation of7-ethoxycarbonyl-5-hydroxy-3-methyl-s-triazolo[4,3-a]pyrimidine

A suspension of 14.7 g of 3-amino-5-methyl-s-triazole and 26.8 g ofethyl acetylenedicarboxylate in 120 ml of ethanol was refluxed for threehours, the reaction mixture was allowed to stand at room temperature forone hour, and the formed crystals were collected by filtration. Thefiltrate was concentrated and the residue was recrystallized fromdichloromethane, and the crystals were joined with those obtained above.Purification by silica gel chromatography gave 10.8 g of the objectivecompound as colorless crystals.

M.P.: 201.1°-203.2° C.

(Step 2)

Preparation of5-chloro-7-ethoxycarbonyl-3-methyl-s-triazolo[4,3-a]pyrimidine

To a suspension of the product obtained in Step 1 (4.3 g) in 50 ml ofphosphorus oxychloride was dropwise added 2.6 g of N,N-dimethylanilineat room temperature. The mixture was heated at 80° C. for one hour,excess phosphorus oxychloride was removed by distillation under reducedpressure, and the remaining reddish brown oil was shaken with 300 mldichloromethane and 300 ml of water. The pH was adjusted to 7 to 8 withsaturated sodium bicarbonate solution, the dichloromethane layer wascollected, and the aqueous layer was again extracted with 200 ml offresh dichloromethane. The chloroform layers were joined together,washed with saturated sodium chloride solution and dried over anhydrousmagnesium sulfate. The dried filtrate was concentrated under reducedpressure, and the oily product left was purified by silica gelchromatography, giving 4.2 g of the objective compound as faint yellowcrystals.

M.P.: 107.7°-109.7° C.

(Step 3)

Preparation of7-ethoxycarbonyl-5-mercapto-3-methyl-s-triazolo[4,3-a]pyrimidine

The product obtained in Step 2 (4.0 g) was added at a time under icecooling to a solution of 4.0 g of sodium hydrosulfide in 100 ml of waterwith stirring in nitrogen, and the mixture was stirred at roomtemperature overnight. The resulting solution was acidified to pH 1.0with 6N hydrochloric acid, and the separated crystals were collected byfiltration and recrystallized from ethanol, affording 3.2 g of theobjective compound as orange crystals.

M.P.: 206.1°-207.5° C.

(Step 4)

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(7-carboxy-3-methyl-s-triazolo[4,3-a]pyrimidin-5-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

A solution of the product obtained in Step 3 (1.0 g and sodiumbicarbonate (0.7 g) in 30 ml of 0.1M phosphate buffer (pH 6.4) washeated at 40° C. with stirring. The product obtained in Step 2 ofExample 7 (2.0 g) was added, and the mixture was heated at 60° C. forsix hours while maintaining the pH between 6.8 and 7.2. After cooling toroom temperature, the resulting solution was washed with 50 ml of ethylacetate and the pH was adjusted to 2.6 with 1N hydrochloric acid. Theformed crystals were collected by filtration and washed with 30 ml ofwater and with 30 ml of methanol in that order, affording 1.3 g of theobjective compound as faint yellow crystals.

IR (KBr, cm⁻¹): 1770, 1600, 1360, 1040.

NMR (DMSO-d₆, δ): 9.6 (1H, d, 8 Hz), 7.4 (1H, s), 6.7 (1H, s) 3.8 (3H,s), 2.5 (3H, s).

EXAMPLE 53

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(7-carboxy-5-hydroxy-s-triazolo[4,3-a]pyrimidin-3-yl)thiomethyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid (Compound 21)

(Step 1)

Preparation of5-hydroxy-3-mercapto-7-methoxycarbonyl-s-triazolo[4,3-a]pyrimidine

A mixture of 15.1 g of 3-amino-5-mercapto-s-triazole, 18.9 g of dimethylacetylenedicarboxylate and 100 ml of ethanol was refluxed for 90minutes. The objective compound (29 g) was obtained by collecting thecrystals separated out upon cooling the reaction mixture.

(Step 2)

Preparation of7-carboxy-5-hydroxy-3-mercapto-s-triazolo[4,3-a]pyrimidine

The product obtained in Step 1 (4.5 g) was added to a solution of 1.7 gpotassium hydroxide in 50 ml water, and the mixture was refluxed for twohours. After cooling to room temperature, the solution was washed with50 ml of ethyl acetate, the pH was adjusted to 1.0 with hydrochloricacid, and the formed crystals were collected by filtration, affording3.9 g of the objective compound.

(Step 3)

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(7-carboxy-5-hydroxy-s-triazolo[4,3-a]pyrimidin-3-yl)thiomethyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

Starting from the product obtained in Step 2 (6.7 g) and the productobtained in Step 2 of Example 7 (15 g) and using 240 ml of 0.1Mphosphate buffer (pH 6.4) and 8.0 g of sodium bicarbonate, 3 g of theobjective compound was obtained in a manner similar to Step 4 of Example37.

IR (KBr, cm⁻¹): 1775, 1675, 1530, 1360, 1040.

NMR (DMSO-d₆, δ): 9.7 (1H, d, 8 Hz), 7.2 (2H, bs), 7.1 (1H, s), 6.7 (1H,s), 6.0-5.7 (1H, m), 5.3-4.9 (1H, m).

EXAMPLE 54

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(7-carboxy-striazolo[1,5-c]pyrimidin-5-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

(Step 1)

Preparation of 2-thiomethyl-4-carboxy-6-chloropyrimidine

S-methylthioorotic acid (13.0 g) was dropwise added to 80 ml ofphosphorus oxychloride under ice cooling, the mixture was stirred atroom temperature and then refluxed for two hours, and excess phosphorusoxychloride was removed by distillation under reduced pressure. Theremaining red oil was shaken with 200 ml of ethyl acetate and 150 ml ofwater, the organic layer was separated and the aqueous layer was againextracted with 200 ml of fresh ethyl acetate. The organic layers werejoined together and washed twice with 200 ml of saturated sodiumbicarbonate solution, then with saturated sodium chloride solution, anddried over anhydrous sodium sulfate. The filtrate was concentrated underreduced pressure to about 20 ml and the residue was recrystallized from50 ml of n-hexane, and the formed crystals were collected by filtration,affording 12.3 g of the objective compound as faint yellow crystals.

(Step 2)

Preparation of 4-carboxy-6-hydrazino-2-thiomethyl pyrimidine

A mixture of the product obtained in Step 1 (4.0 g) and hydrazinemonohydrate was stirred at room temperature for one hour, the resultingsolution was concentrated under reduced pressure, and the formedcrystals were collected by filtration and washed with 50 ml of ethanol,then with 50 ml of ether, giving the objective compound as colorlesscrystals.

(Step 3)

Preparation of 7-carboxy-5-thiomethyl-s-triazolo[1,5-c]pyrimidine

A mixture of the product obtained in Step 2 (2.0 g) and formic acid (40ml) was refluxed for 3.5 hours, the reaction mixture was allowed tostand at room temperature for 2 hours, and the formed crystals werecollected by filtration. The resulting crystals were dissolved in 40 mlof acetic acid and the mixture was refluxed for 5 hours. Afterconcentration under reduced pressure, the residue was dissolved in asmall amount of saturated sodium bicarbonate solution and the solutionwas neutralized with 1N hydrochloric acid. The formed crystals werecollected by filtration and washed with 30 ml of ethanol, then with 30ml of ether, giving 1.1 g of the objective compound as colorlesscrystals.

(Step 4)

Preparation of 7-carboxy-5-mercapto-s-triazolo [1,5-c]pyrimidine

A mixture of the product obtained in Step 3 (0.86 g), sodiumhydrosulfide (1.31 g) and glycerol (5 ml) was stirred at 130° C. for onehour. After cooling to room temperature, the resulting yellow solutionwas poured into 40 ml of water, then acidified to pH 2 to 3 with 1Nhydrochloric acid. The formed crystals were collected by filtration andwashed with 5 ml of water, then with 5 ml of ethanol, affording 0.7 g ofthe objective compound as faint yellow crystals.

(Step 5)

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(7-carboxy-s-triazolo[1,5-c]pyrimidin-5-yl)thiomethyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

A mixture of the product obtained in Step 4 (0.34 g), sodium bicarbonate(0.53 g) and 0.1M phosphate buffer (15 ml) was heated at 40° C. withstirring. The product in Step 2 of Example 7 (1.0 g) was added over aperiod of 30 minutes, and the mixture was heated at 60° C. for fivehours while maintaining the pH between 6.8 and 7.2. After cooling toroom temperature, the resulting brown solution was washed with 10 ml ofethyl acetate and the pH was adjusted to 2.0 with 1N hydrochloric acid,and the formed crystals were collected and washed with 5 ml of methanol,affording 0.5 g of the objective compound as light brown crystals.

IR (KBr, cm⁻¹): 1770, 1630, 1525, 1470, 1400, 1040.

NMR (DMSO-d₆, δ): 9.6 (1H, d, 8 Hz), 8.8 (1H, s), 8.2 (1H, s), 7.2 (2H,bs), 6.7 (1H, s), 5.8 (1H, dd, 8 Hz, 5 Hz), 5.1 (1H, d, 5 Hz), 4.3 (2H,bs), 3.8 (3H, s).

EXAMPLE 55

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(7-amino-s-triazolo[1,5-c]pyrimidin-5-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid (Compound 22)

(Step 1)

Preparation of 7-amino-5-mercapto-s-triazolo[1,5-c]pyrimidine

A mixture of 1,4,6-triamino-2(1H)-pyrimidinethione (2.0 g) and 40 ml offormic acid was refluxed for seven hours. After concentrating underreduced pressure, 80 ml of water was added to the residue, the mixturewas refluxed for one hour, and the crystals formed upon cooling werecollected by filtration and washed with methanol, giving 1.6 g of theobjective compound as faint yellow crystals.

(Step 2)

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3[(7-amino-striazolo[1,5-c]pyrimidin-5-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

A mixture of the product obtained in Step 1 (0.35 g), sodium bicarbonate(0.35 g) and 0.1M phosphate buffer (15 ml) was heated at 40° C. withstirring. The product obtained in Step 2 of Example 7 (1.0 g) was addedover a period of 30 minutes, and the mixture was heated at 60° C. forfive hours while maintaining the pH between 6.8 and 7.2. After coolingto room temperature, the resulting brown solution was washed with 10 mlof ethyl acetate, the pH was adjusted to 3.0 with 1N hydrochloric acid,and the separated crystals were collected and washed with 10 ml of 60%aqueous acetone, 5 ml of water and 5 ml of acetone in that order,affording 0.3 g of the objective compound as faint yellow crystals.

IR (KBr, cm⁻¹): 1770, 1680, 1620, 1540, 1380, 1350, 1040.

NMR (DMSO-d₆, δ): 9.6 (1H, d, 8 Hz), 8.2 (1H, s), 7.2 (2H, bs), 6.7 (1H,s), 5.8 (1H, dd, 8 Hz, 5 Hz), 5.2 (1H, d, 5 Hz), 3.8 (3H, s).

EXAMPLE 56

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(7-methyl-s-triazolo[1,5-c]pyrimidin-5-yl)thiomethyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

(Step 1)

Preparation of 5-mercapto-7-methyl-s-triazolo[1,5-c]pyrimidine

A mixture of 4-hydrazino-2-mercapto-6-methylpyrimidine (2.0 g) and 30 mlof formic acid was refluxed for three hours. After concentrating underreduced pressure, the residue was recrystallized from ether, and thecrystals were collected by filtration, giving 1.85 g of the objectivecompound as faint yellow crystals.

(Step 2)

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(7-methyl-s-triazolo[1,5-c]pyrimidin-5-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

A mixture of the product obtained in Step 1 (0.29 g), sodium bicarbonate(0.53 g) and 0.1M phosphate buffer (15 ml) was heated at 40° C. withstirring. The product obtained in Step 2 of Example 7 (1.0 g) was addedover a period of 30 minutes, and the mixture was heated at 60° C. forfive hours while maintaining the pH between 6.8 and 7.2. After coolingto room temperature, the resulting solution was washed with 10 ml ofethyl acetate and the pH was adjusted to 2.0 with 1N hydrochloric acid,and the formed crystals were collected and washed with 10 ml ofmethanol, affording 0.51 g of the objective compound as light browncrystals.

IR (KBr, cm⁻¹): 1770, 1655, 1615, 1530, 1470, 1385, 1040.

NMR (DMSO-d₆, δ): 9.6 (1H, d, 8 Hz), 8.6 (1H, s), 7.5 (1H, s), 7.2 (2H,bs), 6.7 (1H, s), 5.8 (1H, dd, 8 Hz, 5 Hz), 5.1 (1H, d, 5 Hz), 3.8 (3H,s), 2.5 (3H, s).

EXAMPLE 57

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl-2-(Z-methoxyimino)acetamido]-3-[(2-carboxy-7-methyl-s-triazolo[1,5-c]pyrimidin-5-yl)thiomethyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

(Step 1)

Preparation of 4-hydrazino-2-mercapto-6-methylpyrimidine

Hydrazine monohydrate (6.4 ml) was added dropwise to a suspension of2,4-dimercapto-6-methylpyrimidine (7.0 g) in 100 ml of ethanol at roomtemperature, the mixture was refluxed for two hours, and the crystalsformed upon cooling were collected by filtration and washed with 100 mlof ethanol, giving 6.4 g of the objective compound as yellow crystals.

(Step 2)

Preparation of 4-ethyloxalylhydrazino-2-mercapto-6-methylpyrimidine

Ethyloxalyl chloride (2.15 ml) was added dropwise to an ice-cooledsuspension of the product obtained in Step 1 (3.0 g) in 50 ml ofpyridine over a period of minutes, and the mixture was stirred under icecooling for one hour. The temperature was allowed to rise slowly to roomtemperature, and stirring was continued for an additional one hour. Theformed crystals were collected by filtration and washed with 50 ml ofethanol, affording 4.0 g of the objective compound as colorlesscrystals.

(Step 3)

Preparation of2-ethoxycarbonyl-5-mercapto-7-methyl-s-triazolo[1,5-c]pyrimidine

A mixture of the product obtained in Step 2 (2.4 g) and 10 ml of aceticacid was refluxed for six hours. After cooling to room temperature, theinsoluble matters were filtered off and the filtrate was concentrated invacuo. The residue was dissolved in a small amount of methanol, andether was added to cause crystallization, giving 1.6 g of the objectivecompound as faint yellow crystals.

(Step 4)

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(2-carboxy-7-methyl-s-triazolo[1,5-c]pyrimidin-5-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

A mixture of the product obtained in Step 3 (0.42 g), sodium bicarbonate(0.53 g) and 0.1M phosphate buffer (15 ml) was heated at 40° C. withstirring. The product obtained in Step 2 of Example 7 (1.0 g) was addedover a period of 30 minutes, and the mixture was heated at 60° C. forsix hours while maintaining the pH at 6.8 to 7.2. After cooling to roomtemperature, the resulting solution was washed with 10 ml of ethylacetate and the pH was adjusted to 2.0 with 1N hydrochloric acid. Theformed crystals were collected and recrystallized from methanol/ether,affording 0.41 g of the objective compound as faint yellow crystals.

IR (KBr, cm⁻¹): 1770, 1735, 1670, 1640, 1535, 1370, 1255, 1040.

NMR (DMSO-d₆, δ): 9.6 (1H, d, 8 Hz), 7.5 (1H, s), 7.2 (2H, bs), 6.7 (1H,s), 5.8 (1H, dd, 8 Hz, 5 Hz), 5.1 (1H, d, 5 Hz) 3.8 (3H, s), 2.6 (3H,s).

EXAMPLE 58

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(5-hydroxy-7-methyl-s-triazolo[4,3-c]pyrimidin-3-yl)-thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid (Compound 23)

(Step 1)

Preparation of 2-hydroxy-4-mercapto-6-methylpyrimidine

6-Methyluracil (25.0 g) was suspended in 1 liter of distilled pyridinewith stirring and heated at 50° C. into solution. Phosphoruspentasulfide (12.6 g) was then added, and the mixture was refluxed for20 hours. The solution was concentrated under reduced pressure, then theresidue was refluxed with 500 ml of ethanol for one hour. Insolublematerials were removed by filtration and the filtrate was concentratedunder reduced pressure. The residue was recrystallized from ethanol,affording 5.5 g of the objective compound as colorless crystals.

(Step 2)

Preparation of 4-hydrazino-2-hydroxy-6-methylpyrimidine

The product obtained in Step 1 (3.0 g) was suspended in 30 ml of ethanolat room temperature. Hydrazine monohydrate (3.17 g) was added dropwiseto this suspension and the mixture was refluxed for two hours. Aftercooling to room temperature, the formed crystals were collected byfiltration and washed with 20 ml of ethanol, giving 2.6 g of theobjective compound as red crystals.

(Step 3)

Preparation of 5-hydroxy-3-mercapto-7-methyl-s-triazolo[4,3-c]pyrimidine

The product obtained in Step 2 (1.0 g) was added to a solution of 0.29 gof sodium hydroxide in 20 ml of 80% ethanol, 1.31 g of carbon disulfidewas further added, and the mixture was refluxed for 24 hours. Afterconcentrating under reduced pressure, the residue was dissolved in 10 mlof water and the pH was adjusted to 2.0 with 1N hydrochloric acid. Theformed crystals were collected by filtration and washed with 10 ml ofwater and 10 ml of ethanol, affording 0.7 g of the objective compound aspink crystals.

(Step 4)

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(5-hydroxy-7-methyl-s-triazolo[4,3-c]pyrimidin-3-yl)-thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

A mixture of the product obtained in Step 3 (0.38 g), sodium bicarbonate(0.53 g) and 0.1M phosphate buffer (15 ml) was heated at 40° C. withstirring. The product obtained in Step 2 of Example 7 (1.0 g) was addedover a period of 30 minutes, and the mixture was further heated at 60°C. for six hours while maintaining the pH at 6.8 to 7.2. After coolingto room temperature, the resulting brown solution was washed with 20 mlof ethyl acetate and the pH was adjusted to 2.0 with lN hydrochloricacid. The formed crystals were collected and washed with 10 ml of 60%aqueous acetone, 10 ml of water and 10 ml of acetone in that order,affording 0.3 g of the objective compound as yellow crystals.

IR (KBr, cm⁻¹): 1770, 1735, 1670, 1640, 1535, 1370, 1255, 1040, 760.

NMR (DMSO-d₆, δ): 12.0 (1H, s), 9.6 (1H, d, 8 Hz), 7.2 (2H, bs), 6.7(1H, s), 6.5 (1H, s), 5.8 (1H, dd, 8 Hz, 5 Hz), 5.2 (1H, d, 5 Hz), 3.8(3H, s), 2.5 (3H, s).

EXAMPLE 59

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(7-methyl-5-oxo-5H-l,3,4-thiadiazolo[3,2-a]pyrimidin-2-yl)thiomethyl]8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid (Compound 24)

(Step 1)

Preparation of2-mercapto-7-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine

To a solution of 2-amino-5-mercapto-l,3,4-thiadiazole (4.0 g) and ethylacetoacetate (4.3 g) in 50 ml ethanol, piperidine (2.55 g) was slowlyadded. The mixture was refluxed for seven hours and then allowed tostand overnight at room temperature. The formed crystals were collectedby filtration and dissolved in 100 ml of water. The pH was adjusted to2.0, and the formed crystals were collected and washed with 20 ml ofwater, affording 3.8 g of the objective compound as colorless crystals.

(Step 2)

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(7-methyl-5-oxo-5H-l,3,4-thiadiazolo[3,2-a]pyrimidin-2-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

A mixture of the product obtained in Step 1 (0.42 g), sodium bicarbonate(0.53 g) and 0.1M phosphate buffer (20 ml, pH 6.4) was heated at 40° C.with stirring. The product obtained in Step 2 of Example 7 (1.0 g) wasslowly added and the mixture was heated at 60° C. for six hours whilemaintaining the pH at 6.5 to 7.5. After cooling to room temperature, theresulting solution was washed with 30 ml of ethyl acetate and the pH wasadjusted to 2.0 with 1N hydrochloric acid. The formed crystals werecollected and washed twice with 10 ml of water and once with 10 ml of50% aqueous acetone, affording 0.68 g of the objective compound as faintyellow crystals.

IR (KBr, cm⁻¹): 1760, 1660, 1620, 1570, 1390, 1030.

NMR (DMSO-d₆, δ): 9.6 (1H, d, 8 Hz), 7.4 (1H, s), 7.2 (2H, bs), 6.7 (1H,s), 5.8 (1H, dd, 8 Hz, 5 Hz), 5.1 (1H, d, 5 Hz) 4.2 (1H, d), 3.8 (3H,s), 2.3 (3H, s)

EXAMPLE 60

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(6-carboxy-5-oxo-5H-b1,3,4-thiadiazolo[3,2-a]pyrimidin-2-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

(Step 1)

Preparation of6-ethoxycarbonyl-2-mercapto-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine

A mixture of 2-amino-5-mercapto-1,3,4-thiadiazole (6.7 g), diethylethoxymethylenemalonate (16.2 g) and dimethylformamide (80 ml) wasrefluxed for 16 hours. After removing the solvent by distillation underreduced pressure, the residue was recrystallized from methanol, giving10.3 g of the objective compound as colorless crystals.

(Step 2)

Preparation of6-carboxy-2-mercapto-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine

The product obtained in Step 1 (9.1 g) was added to a solution of 4.0 gof potassium hydroxide in 200 ml of water, and the mixture was heated at60° C. for 30 minutes. After cooling to room temperature, the solutionwas washed with 200 ml of ethyl acetate and the pH was adjusted to 1.0with hydrochloric acid. The formed crystals were collected by filtrationand washed with ether, affording 6.5 g of the objective compound.

(Step 3)

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(6-carboxy-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-2-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

Starting from the product obtained in Step 2 (7.2 g) and the productobtained in Step 2 of Example 7 (15 g) in 240 ml of 0.1M phosphatebuffer (pH 6.4) and 8.0 g of sodium bicarbonate, 4.8 g of the objectivecompound was obtained in a manner similar to Step 4 of Example 37.

IR (KBr, cm⁻¹): 1775, 1670, 1530, 1360, 1040.

NMR (DMSO-d₆, δ): 9.7 (1H, d, 8 Hz), 8.6 (1H, s), 7.3 (2H, bs), 6.7 (1H,s), 5.9 (1H, dd, 8 Hz, 5 Hz), 5.2 (1H, d, 5 Hz), 4.4 (2H, bs), 3.8 (3H,s), 3.6 (2H, bs)

EXAMPLE 61

Preparation of(6R,7R)-7-[2-(2-triphenylmethylamino-4-thiazolyl)-2-(Z-benzoyloxyimino)acetamido]-3-[(2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid diphenylmethyl ester

To an ice-cooled solution of the product obtained in Example 17 (0.5 g)in 12 ml of anhydrous dichloromethane, was added anhydrous potassiumcarbonate (0.07 g) with stirring, and the mixture was stirred undercooling with ice. A solution of benzoyl chloride (0.07 g) indichloromethane (7 ml) was added over a period of 10 minutes and themixture was stirred for one hour under ice cooling. The insolublematters were filtered off and washed twice with 2 ml of dichloromethane,and the washings were joined with the filtrate. After concentrating thedichloromethane solution under reduced pressure, the brown residue (0.5g) was crystallized with 10 ml of ether, affording 0.25 g of theobjective compound as faint yellow crystals.

IR (KBr, cm⁻¹): 1791, 1743, 1596, 1525, 1521, 1507, 1498, 1450, 1242,1202, 1182.

NMR (DMSO-d₆, δ): 10.0 (1H, d, 8 Hz), 9.0 (1H, s), 8.1-8.0 (2H, m)7.5-7.1 (42H, m), 6.0 (1H, dd, 8 Hz, 5 Hz), 5.3 (1H, d, 5 Hz), 4.3 (2H,bs), 3.7 (2H, bs), 2.5(3H, s).

EXAMPLE 62

Preparation of(6R,7R)-7-[2-(2-triphenylmethylamino-4-thiazolyl)-2-(Z-benzoyloxyimino)acetamido]-3-[2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid diphenylmethyl ester

Triethylamine (32 μl) was added to a solution of benzoic acid (23 mg) inanhydrous dichloromethane (5 ml), and the resulting faint yellowsolution was cooled to -10° C. Ethyl chloroformate (18 μl) was added tothis solution and the mixture was stirred at that temperature for twohours. The resulting slurry was cooled to -40° C., and a solution of theproduct obtained in Example 17 (0.2 g) in 5 ml of dichloromethane wasadded. The mixture was stirred at that temperature for 20 minutes and at-10° C. for 20 minutes, and the temperature was allowed to rise to 0° C.over a period of 30 minutes. After removing the solvent by distillationunder reduced pressure, 100 ml of ethyl acetate was added to the brownresidue (0.25 g). The mixture was washed with 30 ml of 1N hydrochloricacid, 30 ml of saturated sodium bicarbonate solution and 50 ml ofsaturated sodium chloride solution in that order, and then dried overanhydrous sodium sulfate. Then the dried solution was concentrated underreduced pressure, and the brown residue (0.25 g) was purified by silicagel column chromatography using n-hexane/ethyl acetate as the eluent.

IR (KBr, cm⁻¹): 1791, 1743, 1596, 1525, 1521, 1507, 1498, 1450, 1242,1202, 1182.

NMR (DMSO-d₆, δ): 10.0 (1H, d, 8 Hz), 9.0 (1H, s), 8.1-8.0 (2H, m)7.5-7.1 (42H, m), 6.0 (1H, dd, 8 Hz, 5 Hz), 5.3 (1H, d, 5 Hz), 4.3 (2H,bs), 3.7 (2H, bs), 2.5 (3H, s).

These analytical results are in exact agreement with those obtained inExample 61.

EXAMPLE 63

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-benzoyloxyimino)acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid (Compound 25)

To an ice-cooled solution of the product obtained in Example 61(0.2 g)in anhydrous dichloroethane was added 0.11 ml of anisole and 0.22 ml oftrifluoroacetic acid with stirring. The mixture was stirred undercooling with ice for 1.5 hours and then at room temperature for twohours. After concentrating the resulting solution under reducedpressure, 10 ml of ether was added to the reddish brown residue. Theformed crystals were collected by filtration, affording 0.1 g of theobjective compound as faint yellow crystals.

IR (KBr, cm⁻¹): 1778, 1735, 1619, 1598, 1200, 1020.

NMR (DMSO-d₆, δ): 10.0 (1H, d, 8 Hz), 8.2-8.0 (2H, m), 7.6 (5H, m), 7.40(1H, s), 7.1 (1H, s), 5.9 (1H, dd, 5 Hz, 8 Hz), 5.3 (1H, d, 5 Hz), 4.4(2H, bs), 4.1 (2H, bs), 2.6 (3H, s).

EXAMPLE 64

Preparation of2-(2-triphenylmethylamino-4-thiazolyl)-2-(Z-benzoyloxyimino)acetic acid.

2-(2-Triphenylmethylamino-4-thiazolyl)-2-(Z-hydroxyimino)acetic acid (10g) was suspended in 140 ml of anhydrous dichloromethane, and 6.7 ml oftriethylamine was added to this suspension under ice cooling withstirring. To the resulting solution was added a solution of benzoylchloride (3.2 g) in dichloromethane (20 ml). The mixture was stirred atroom temperature for one hour, the insoluble matters were filtered off,and the filtrate was washed twice with 20ml 1N hydrochloric acid and 30ml of saturated sodium chloride solution each and dried over anhydroussodium sulfate. The dried filtrate was concentrated under reducedpressure, and the brown viscous residue (12 g) was purified by silicagel column chromatography using chloroform containing 10 to 15% methanolas eluent, giving 3 g of the objective compound as light brown crystals.

NMR (DMSO-d₆, δ): 9.0 (1H, s), 7.6-7.2 (21H, m).

EXAMPLE 65

Preparation of(6R,7R)-7-[2-(2-triphenylmethylamino-4-thiazolyl)-2-(Z-benzoyloxyimino)acetamido]-3-[(2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid diphenylmethyl ester

The product obtained in Example 64 (3 g) and the product obtained inExample 15 (4.3 g) were dissolved in anhydrous dichloromethane (200 ml).The faint yellow solution was cooled to -30° C. with stirring, and asolution of dicyclohexylcarbodiimide (1.2 g) in anhydrousdichloromethane (30 ml) was added by dropwise over a period of fiveminutes. The mixture was allowed to stand at 0° C. for nine hours, theinsoluble matters were filtered off, and the filtrate was washed with 50ml of 1N aqueous citric acid, 50 ml of saturated sodium bicarbonatesolution and 80 ml of saturated sodium chloride solution in that order,and dried over anhydrous sodium sulfate. The dried filtrate wasconcentrated in vacuo, and the yellow viscous residue left (6.8 g) waspurified by silica gel column chromatography using ethyl acetate hexaneas eluent, yielding 5 g of the objective compound as faint yellowcrystals.

IR (KBr, cm⁻¹): 1791, 1743, 1596, 1525, 1521, 1507, 1498, 1450, 1242,1202, 1182.

NMR (DMSO-d₆, δ): 10.0 (1H, d, 8 Hz), 9.0 (1H, s), 8.1-8.0 (2H, m),7.5-7.1 (42H, m), 6.0 (1H, dd, 8 Hz, 5 Hz), 5.3 (1H, d, 5 Hz), 4.3 (2H,bs), 3.7 (2H, bs), 2.5 (3H, s).

These analytical results are in exact agreement with those obtained inExample 62.

EXAMPLE 66

Preparation of(6R,7R)-7-[2-(2-triphenylmethylamino-4-thiazolyl)-2-[Z-(2-pyrrolecarbonyl)oxyimino]acetamido]-3-[(2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid diphenylmethyl ester.

Potassium carbonate (0.1 g) was added all at once to an ice-cooledsolution of the product obtained in Example 17 (0.7 g) in 17 ml ofanhydrous dichloromethane. A solution of 0.078 g of pyrrole-2-carboxylicacid chloride in 10 ml of dichloromethane was added by dropwise over aperiod of five minutes, and the mixture was stirred under ice coolingfor 40 minutes and then at room temperature for three hours. Afterfiltering off the insoluble matters, the filtrate was concentrated underreduced pressure, and the yellow residue was purified by silica gelcolumn chromatography, giving 0.3 g of the objective compound as faintyellow crystals.

IR (KBr, cm⁻¹): 1786, 1739, 1595, 1526, 1449, 1375, 1058, 745.

(DMSO-d₆, δ): 12.0 (1H, brs), 9.8 (1H, d, 8 Hz), 9.0 (1H, s), 7.8-6.9(41H, m), 6.2 (1H, m), 6.0 (1H, dd, 8 Hz, 5 Hz), 5.3 (1H, d, 5 Hz), 4.2(2H, bs), 3.7 (2H, bs), 2.5 (3H, s).

EXAMPLE 67

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-(2-pyrrolecarbonyl)oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid (Compound 26)

The product obtained in Example 66 (0.3 g) was dissolved in 2.5 ml ofdichloroethane. Then 0.16 ml of anisole and 0.32 ml of trifluoroaceticacid were added dropwise to the solution in this order under icecooling, and the resulting yellow solution was stirred at roomtemperature for five hours. After concentrating under reduced pressure,the residue was subjected to crystallization with 30 ml of ether,affording 0.1 g of the objective compound as faint yellow crystals.

IR (KBr, cm⁻¹): 1774, 1733, 1700, 1637, 1112, 1063, 935, 748.

NMR (DMSO-d₆, δ): 12.0 (1H, s), 10.0 (1H, d, 8 Hz), 7.4 (1H, s), 7.3-7.0(4H, m), 7.1 (1H, s), 6.2 (1H, m), 6.0 (1H, dd, 8 Hz, 5 Hz), 5.3 (1H, d,5 Hz), 4.5 (2H, bs), 3.7 (2H, bs), 2.6 (3H, s).

EXAMPLE 68

Preparation of(6R,7R)-3-acetoxymethyl-7-[2-amino-4-thiazolyl-2-[Z-(3,4-methylenedioxybenzoyl)oxyimino]acetamido]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

(Step 1)

Preparation of(6R,7R)-3-acetoxymethyl-7-[2-(2-triphenylmethylamino-4-thiazolyl)-2-[Z-(3,4-methylenedioxybenzoyl)oxyimino]acetamido]-8-oxo-5-thia-1-azabicyclo[4.20]oct-2-ene-2-carboxylic acid diphenylmethyl ester

The product obtained in Example 27 (8.0 g) and(6R,7R)-3-acetoxymethyl-7-amino-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid diphenylmethyl ester (6.7 g) were dissolved in anhydrousdichloromethane (150 ml), the faint yellow solution was cooled on ice,and dicyclohexylcarbodiimide (3.2 g) was added. The mixture was stirredunder ice cooling for one hour and then at room temperature for ninehours, the insoluble matters were filtered off, and the filtrate waswashed with 100 ml of 1N aqueous citric acid, 100 ml of saturated sodiumbicarbonate solution and 100 ml of saturated sodium chloride solution inthat order, and dried over anhydrous sodium sulfate. The dried filtratewas concentrated in vacuo, and the yellow viscous residue (14.0 g) waspurified by silica gel column chromatography using ethylacetate/n-hexane as eluent, yielding 11.5 g of the objective compound asfaint yellow crystals.

IR (KBr, cm⁻¹): 1780, 1730, 1520, 1260, 1030, 750, 700.

NMR (DMSO-d₆, δ): 10.6 (1H, d, 8 Hz), 9.0 (1H, s), 7.8-7.0 (30H, m), 6.1(2H, s), 5.8 (1H, dd, 8 Hz, 5 Hz), 5.2 (1H, d, 5 Hz), 4.8 (2H, ABq), 3.6(2H, bs), 2.0 (3H, s).

(Step 2)

Preparation of(6R,7R)-3-acetoxymethyl-7-[2-amino-4-thiazolyl-2-[Z-(3,4-methylenedioxybenzoyl)oxyimino]acetamido]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

Removal of the protecting groups from the compound obtained in Step 1(11.5 g) in a manner similar to Example 26 gave 6.1 g of the objectivecompound as faint yellow crystals.

IR (KBr, cm⁻¹): 1780, 1740, 1450, 1265, 1040, 760 .

NMR (DMSO-d₆, δ): 10.1 (1H, d, 8 Hz), 7.7 (1H, dd, 8 Hz, 1 Hz), 7.4 (1H,d, 1 Hz), 7.3 (2H, bs), 7.1 (1H, s), 7.0 (1H, d, 8 Hz), 6.1 (2H, s), 5.8(1H, dd, 8 Hz, 5 Hz), 5.2 (1H, d, 5 Hz), 4.8 (2H, ABq), 3.6 (2H, bs),2.0 (3H, s).

EXAMPLE 69

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-(3,4-methylenedioxybenzoyl)oxyimino]acetamido]-3[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

To a solution of the compound obtained in Example 1 (1.5 g) and sodiumbicarbonate (2.2 g) in 70 ml of 0.1M phosphate buffer (pH 6.4) was added5.0 g of the product obtained in Example 68, and the mixture was heatedat 60° C. for six hours with stirring. After cooling to roomtemperature, the reaction mixture was washed with 50 ml of ethylacetate, the aqueous layer was acidified to pH 3.0 with 6N hydrochloricacid, and the formed crystals were collected and washed twice with 50 mleach of methanol and aqueous acetone, affording 1.5 g of the objectivecompound as faint yellow crystals.

IR (KBr, cm⁻¹): 3400, 1774, 1739, 1580, 1500, 1250, 1030, 730.

NMR (DMSO-d₆, δ): 10.1 (1H, d, 8 Hz), 7.6 (1H, d, 9 Hz), 7.4 (1H, s),7.4-7.2 (1H, m), 7.1 (1H, s), 7.0 (1H, d, 9 Hz), 6.1 (2H, s), 6.0 (1H,dd, 8 Hz, 5 Hz), 5.2 (1H, d, 5 Hz), 4.5 (2H, bs), 3.8 (2H, bs), 2.6 (3H,s).

EXAMPLE 70

Preparation of(6R,7R)-7-[2-(2-triphenylmethylamino-4-thiazolyl)-2-[Z-(3,4-diacetoxybenzoyl)oxyimino]acetamido]-3-[(2-diphenylmethyloxycarbonyl-5-methyl-s-triazolo[l,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid diphenylmethyl ester.

Potassium carbonate (0.43 g) was added all at once to an ice-cooledsolution of the product obtained in Example 17 (3.0 g) in 60 ml ofanhydrous dichloromethane. A solution of 0.79 g of 3,4-diacetoxybenzoylchloride in 40 ml of dichloromethane was added dropwise over a period of15 minutes, and the mixture was stirred under ice cooling for one hourand then at room temperature for one hour. After filtering off theinsoluble matters, the filtrate was washed with 20 ml of water and 10 mlof saturated sodium chloride solution. The organic layer was dried overanhydrous sodium sulfate, and the solvent was removed by distillationunder reduced pressure, and the residue was treated with ether. Theformed crystals were washed twice with ether, giving 3.2 g of theobjective compound as yellow crystals.

IR (KBr, cm⁻¹): 1779, 1744, 1498, 1279, 1201, 1187, 700.

NMR (DMSO-d₆, δ): 10.0 (1H, d, 8 Hz), 9.0 (1H, s), 7.8-6.8 (42H, m), 5.9(1H, dd, 8 Hz, 5 Hz), 5.3 (1H, d, 5 Hz), 4.2 (2H, bs), 3.5 (2H, bs), 2.5(3H, s), 2.3 (3H, s), 2.2 (3H, s).

EXAMPLE 71

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-(3,4-diacetoxybenzoyl)oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

(Compound 27)

The product obtained in Example 70 (3.2 g) was dissolved in 20 ml ofdichloroethane. Then 1.7 ml of anisole, 3.3 ml of trifluoroacetic acidand two drops of water were dropwise added to the solution in this orderby under ice cooling, and the resulting red solution was stirred at roomtemperature for three hours. After concentrating under reduced pressure,the residue was subjected to crystallization with 40 ml of ether,affording 2.2 g of the objective compound as yellow crystals.

IR (KBr, cm⁻¹): 1773, 1764, 1597, 1509, 1281, 1262, 1207, 1164.

NMR (DMSO-d₆, δ): 10.3 (1H, d, 8 Hz), 7.9 (2H, m), 7.6-7.1 (5H, m), 6.0(1H, dd, 8 Hz, 5 Hz), 5.3 (1H, d, 5 Hz), 4.5 (2H, bs), 3.8 (2H, ABq),2.6 (3H, s), 2.3 (3H, s), 2.2 (3H, s)

EXAMPLE 72

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)-thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid (Compound 2)

(Step 1)

Preparation of(6R,7R)-3-[(2-carboxy-5-methyl-striazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-7-[2(2-chloroacetamido-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

Triethylamine (0.69 g) was added to a solution of2-(2-chloroacetamido-4-thiazolyl)-2-(Z-methoxyimino)acetic acid (1.5 g)in 10 ml of dichloromethane, and 1.2 g of phosphorous pentachloride wasthen added by drops at 0° C. over a period of ten minutes. Afterstirring the mixture at 0° C. for ten minutes and then at roomtemperature for one hour, dichloromethane was removed by distillationunder reduced pressure, the residue was washed twice with 5 ml ofn-hexane to remove excess phosphorus pentachloride, the brown residuewas dissolved in 10 ml of tetrahydrofuran, and the phosphoruspentachloride still left was removed by filtration. This acid chloridesolution in tetrahydrofuran was added dropwise under ice cooling over aperiod of 5 minutes to the solution of the product obtained in Example14 (2.2 g) and bis(trimethylsilyl)acetamide (3.1 g) in 50 ml of drydichloromethane, and the mixture was stirred at room temperature for twohours. After removing the solvent by distillation under reducedpressure, the brown residue was added to a mixture of 25 ml of ethylacetate and 10 ml of water, and the pH was adjusted to 7.5 with sodiumbicarbonate, followed by washing with ethyl acetate. The aqueous layerwas collected, its pH was lowered to 2.0 with 1N hydrochloric acid, thecrystals thus formed were collected by filtration, washed twice with 10ml of water and then once with 5 ml of 50% aqueous acetone, andthoroughly dried, giving 1.8 g of the objective compound as browncrystals.

IR (KBr, cm-1): 1770, 1690, 1600, 1550, 1500, 1040.

NMR (DMSO-d₆,δ): 9.5 (1H, s), 8.1 (1H, d, 8 Hz), 7.4 (1H, s), 6.8 (1H,s), 4.7 (2H, s), 3.8 (3H, s), 2.5 (3H, s).

(Step 2)

Preparation of (6R,7R)-7-[2-(2-amino-4-thiazol

yl)-2-(Z-methoxyimino)acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thio-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid.

The product obtained in Step 1 (1.8 g) was dissolved in 30 ml ofdimethylacetamide, 0.5 g of thiourea was added to this solution at roomtemperature in small portions over a period of ten minutes, and themixture was stirred at room temperature for an additional nine hours.After concentration of the reaction mixture under reduced pressure, 80ml of ethyl acetate and 200 ml of water were added to the brown residue,the pH was adjusted to 7.8 with sodium bicarbonate, and the aqueouslayer was washed with ethyl acetate until no thiourea could be detectedin the aqueous layer. The pH of aqueous layer was lowered to 3.5, thecrystals thus formed were collected by filtration, washed twice with 20ml of water and then once with 5 ml of 50% aqueous acetone, and dried,giving 0.9 g of the objective compound as colorless crystals.

IR (KBr, cm⁻¹): 1770, 1625, 1510, 1040. NMR (DMSO-d₆,δ): 9.6 (1H, d, 8Hz), 7.4 (IH, s), 6.7 (IH, s), 3.8 (3H, s), 2.6 (3H, s).

These analytical results are in exact agreement with those obtained inExample 7.

Example 73

Preparation of (6R,7R)-7-[2-(2-triphenylmethyl-amino-4-thiazolyl)-2-[Z-(3,4,5-triacetoxybenzo-yl)oxyimino]acetamido]-3-[(2-diphenylmethyloxy-carbonyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic aciddiphenylmethyl ester.

Potassium carbonate (0.28 g) was added all at once to an ice-cooledsolution of the product obtained in Example 17 (2.0 g) in 50 ml ofanhydrous dichloromethane. A solution of 0.65 g of3,4,5-triacetoxybenzoyl chloride in 30 ml of dichloromethane was addeddropwise over a period of 5 minutes, and the mixture was stirred underice cooling for 15 minutes. After filtering off the insoluble matters,the solvent was removed by distillation under reduced pressure, and theresidue was treated with ether. The formed crystals were washed twicewith ether, giving 2.3 g of the objective compound as pale yellowcrystals.

IR (KBr, cm⁻¹): 1783, 1750, 1595, 1508, 1323, 1183, 700.

NMR (DMSO-d₆,δ): 10.1 (1H, d, 8 Hz), 9.3 (1H, bs), 7.8-6.8 (4lH, m), 5.9(1H, dd, 8 Hz, 5 Hz), 5.3 (1H, d, 5 Hz), 4.3 (2H, bs), 3.6 (2H, bs), 2.5(3H, s), 2.3 (6H, s), 2.2 (3H, s).

EXAMPLE 74

Preparation of(6R,7R)-7-[2-(2-amino-4-thiazol-yl)-2-[Z-(3,4,5-triacetoxybenzoyl)oxyimino]acet-amido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]-pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-aza-bicyclo [4.2.0]oct-2-ene-2-carboxylicacid.

(Compound 13)

The product obtained in Example 73 (1.7 g) was dissolved in 15 ml ofdichloroethane. Then 0.8 ml of anisole, 1.6 ml of trifluoroacetic acidand two drops of water were added dropwise to the solution in this orderunder ice cooling, and the resulting red solution was stirred at roomtemperature for three hours. After concentrating under reduced pressure,the residue was subjected to crystallization with 40 ml of ether,affording 0.9 g of the objective compound as yellow crystals.

IR (KBr, cm⁻¹): 1779, 1775, 1597, 1509, 1324, 1190, 1055.

NMR (DMSO-d₆,δ): 10.1 (1H, d, 8 Hz), 7.8 (2H, s), 7.4 (1H, s), 7.2 (lH,s), 5.9 (lH, dd, 8 Hz, 5 Hz), 5.2 (lH, d, 5 Hz), 4.5 (2H, bs), 3.7 (2H,ABq), 2.6 (3H, s), 2.4 (3H, s), 2.3 (6H, s).

Typical compounds of this invention are summarized below in Tables4-through 4-f.

                                      TABLE 4-a                                   __________________________________________________________________________     ##STR14##                                                                    Example No.                                                                   (Compound No.)                                                                         R.sup.1                                                                         R.sup.2                                                                             R.sup.3                                                                             R.sup.4                                                                           R.sup.12      R.sup.13                             __________________________________________________________________________    8        H H     CH.sub.3                                                                            H   CH.sub.3      H                                    (1)                                                                           7        H COOH  CH.sub.3                                                                            H   CH.sub.3      H                                    (2)                                                                           9        H H     H     COOH                                                                              CH.sub.3      H                                    (3)                                                                           11       H CH.sub. 2 COOH                                                                      CH.sub.3                                                                            H   CH.sub.3      H                                    (4)                                                                           10       H H     CH.sub.2 COOH                                                                       H   CH.sub.3      H                                    (5)                                                                           12       H H     COOH  H   CH.sub.3      H                                    (6)                                                                           13       H COOH  H     COOH                                                                              CH.sub.3      H                                    (7)                                                                           18       H COOH  CH.sub.3                                                                            H   H             H                                    (8)                                                                           20 (9)   H COOH  CH.sub.3                                                                            H                                                                                  ##STR15##    H                                    22 (10)  H COOH  CH.sub.3                                                                            H                                                                                  ##STR16##    H                                    24 (11)  H COOH  CH.sub.3                                                                            H                                                                                  ##STR17##    H                                    26 (12)  H COOH  CH.sub.3                                                                            H                                                                                  ##STR18##    H                                    32       H COOH  CH.sub.3                                                                            H   COCH.sub.2 SCH.sub.2 CN                                                                     H                                    34       H COOH  CH.sub.3                                                                            H                                                                                  ##STR19##    H                                    36       H COOH  CH.sub.3                                                                            H                                                                                  ##STR20##    H                                    63 (25)  H COOH  CH.sub.3                                                                            H                                                                                  ##STR21##    H                                    67 (26)  H COOH  CH.sub.3                                                                            H                                                                                  ##STR22##    H                                    37       H COOH  CH(CH.sub.3).sub.2                                                                  H   CH.sub.3      H                                    38       H COOH  H     H   CH.sub.3      H                                    (14)                                                                          39       H COOH  CH.sub.3                                                                            CH.sub.3                                                                          CH.sub.3      H                                    40       H CH.sub.3                                                                            COOH  H   CH.sub.3      H                                    41       H CONHNH.sub.2                                                                        CH.sub.3                                                                            H   CH.sub.3      H                                    42       H COOH  OH    H   CH.sub.3      H                                    (15)                                                                          46       H H     OCH.sub.3                                                                           H   CH.sub.3      H                                    (16)                                                                          44       H NH.sub.2                                                                            CH.sub.3                                                                            H   CH.sub.3      H                                    (17)                                                                          45       H SO.sub.3 H                                                                          CH.sub.3                                                                            H   CH.sub.3      H                                    (18)                                                                          43       H H     Cl    H   CH.sub.3      H                                    71 (27)  H COOH  CH.sub.3                                                                            H                                                                                  ##STR23##    H                                    74 (13)  H COOH  CH.sub.3                                                                            H                                                                                  ##STR24##    H                                    __________________________________________________________________________

                                      TABLE 4-b                                   __________________________________________________________________________     ##STR25##                                                                     Example No.                                                                  (Compound No)                                                                            R.sup.1                                                                            R.sup.5                                                                          R.sup.6    R.sup.12                                                                         R.sup.13                                     __________________________________________________________________________    47         H    CH.sub.3                                                                         H          CH.sub.3                                                                         H                                            49         H    H  COOH       CH.sub.3                                                                         H                                            (19)                                                                          48         H    H  COOC.sub.2 H.sub.5                                                                       CH.sub.3                                                                         H                                            50         H    H                                                                                 ##STR26## CH.sub.3                                                                         H                                            __________________________________________________________________________

                  TABLE 4-c                                                       ______________________________________                                         ##STR27##                                                                     Example No.                                                                  (Compound No.) R.sup.1                                                                             R.sup.7    R.sup.12                                                                           R.sup.13                                 ______________________________________                                        51             H     H          CH.sub.3                                                                           H                                        52             H     CH.sub.3   CH.sub.3                                                                           H                                        (20)                                                                          ______________________________________                                    

                  TABLE 4-d                                                       ______________________________________                                         ##STR28##                                                                     Example No.                                                                  (Compound No.)                                                                             R.sup.1                                                                             R.sup.8   R.sup.9                                                                             R.sup.12                                                                             R.sup.13                            ______________________________________                                         54          H     H         COOH  CH.sub.3                                                                             H                                   55           H     H         NH.sub.2                                                                            CH.sub.3                                                                             H                                   (22)                                                                          56           H     H         CH.sub.3                                                                            CH.sub.3                                                                             H                                   57           H     COOH      CH.sub.3                                                                            CH.sub.3                                                                             H                                   ______________________________________                                    

                                      TABLE 4-e                                   __________________________________________________________________________     ##STR29##                                                                     Example No.                                                                  (Compound No.)                                                                           R.sup.1                                                                            R.sup.10                                                                         R.sup.11   R.sup.12                                                                         R.sup.13                                     __________________________________________________________________________    59         H    CH.sub.3                                                                         H          CH.sub.3                                                                         H                                            (24)                                                                          60         H    H  COOH       CH.sub.3                                                                         H                                            __________________________________________________________________________

EXAMPLE NO. 53 (Compound No. 21) ##STR30## EXAMPLE NO. 58 (Compound No.23) ##STR31##

                  TABLE 4-f                                                       ______________________________________                                         Example No.                                                                  (Compound No.)                                                                            R.sup.1  R.sup.12         R.sup.14                                ______________________________________                                        29          (C.sub.6 H.sub.5).sub.3 C                                                               ##STR32##       H                                       27          (C.sub.6 H.sub.5).sub.3 C                                                               ##STR33##       H                                       64          (C.sub.6 H.sub.5).sub.3 C                                                               ##STR34##       H                                       ______________________________________                                    

The following examples detail typical pharmaceutical preparationscontaining the cephalosporin derivatives of the present invention. Theseexamples are not intended to limit the types of compounds to be used,but the methods are applicable to all the compounds of this invention.

EXAMPLE A (Method of manufacturing freeze-dried parenteral injections)

(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid (1.1 g) was dissolved in 22 ml of sterile water containing anequivalent amount of sodium bicarbonate, and 2 ml each of this solutionwas poured into 5-ml ampoules, freeze dried and sealed by ordinarymethods to produce freeze dried preparation for parenteral injections.

EXAMPLE B (Method of manufacturing tablets for oral administration)

Granules were prepared by ordinary method using 250 mg of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-(3,4-diacetoxybenzoyl)oxyimino)acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[l,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2carboxylicacid, 100 mg of lactose, 30 mg of starch and 10 mg of polyvinylpyrrolidone. Starch (30 mg) and magnesium stearate (5 mg) were furtheradded to the granules, and the resulting mixture was compressed intotablets, each piece weighing 425 mg.

EXAMPLE C (Method of manufacturing gelatin capsules for oraladministration)

(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-(2-furancarbonyl)oxyimino)acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (250 mg), water-soluble polyvinylpyrrolidone (15 mg), mannitol (15 mg), talc (15 mg) and magnesiumstearate (5 mg) were uniformly mixed, giving gelatin capsules, eachpiece weighing 300 mg.

What is claimed is:
 1. A compound of the formula (I): ##STR35## andsalts, hydrates and hydrates of salts of said cephalosporin compound;wherein R¹ represents a hydrogen atom or an amino-protecting group; Zrepresents: ##STR36## wherein R² represents a hydrogen atom, a methylgroup, an amino group, a cyano group, a hydroxysulfonyl group, acarboxyl group, a carboxymethyl group, a protected carboxyl group, aprotected carboxymethyl group, a methoxycarbonyl group or a hydrazinocarbonyl group; R³ represents a hydrogen atom, an alkyl group having 1to 3 carbon atoms, a hydroxy group, a methoxy group, a carboxyl group, acarboxymethyl group or a chlorine atom; R⁴ represents a hydrogen atom, amethyl group or a carboxyl group; R⁵ represents a hydrogen atom or amethyl group; R⁶ represents a hydrogen atom, a carboxyl group, anethoxycarbonyl group or a piperidinocarbonyl group; R⁷ represents ahydrogen atom or a methyl group; R8 represents a hydrogen atom or acarboxyl group; R⁹ represents a methyl group, an amino group or acarboxyl group; R¹⁰ represents a hydrogen atom or a methyl group; R¹¹represents a hydrogen atom or a carboxyl group; R¹² represents ahydrogen atom, a methyl group, a hydroxyl-protecting group, acyanomethyl-thioacetyl group a monocyclic carbocyclic aromatic acylgroup which may be substituted by protected or non-protected hydroxygroups or a mono- or dicyclic heterocyclic aromatic acyl group; R¹³represents a hydrogen atom or a carboxyl-protecting group; and a wavyline represents a bond of anti-form or of syn-form.
 2. A compound asclaimed in claim 1 wherein said wavy line represents a bond of syn-form.3. A compound as claimed in claim 1 which is represented by the formula(Ia): ##STR37##
 4. A compound as claimed in claim 3 wherein R² and R⁴each represent a hydrogen atom and R³ represents a methyl group.
 5. Acompound as claimed in claim 3 wherein R² represents a carboxyl group,R³ represents a methyl group and R⁴ represents a hydrogen atom.
 6. Acephalosporin compound as claimed in claim 3 wherein R² and R³ eachrepresent a hydrogen atom and R⁴ represents a carboxyl group.
 7. Acompound as claimed in claim 3 wherein R² represents a carboxymethylgroup, R³ represents a methyl group and R⁴ represents a hydrogen atom.8. A compound as claimed in claim 3 wherein R² and R⁴ each represent ahydrogen atom and R³ represents a carboxymethyl group.
 9. A compound asclaimed in claim 3 wherein R² and R⁴ each represent a hydrogen atom andR³ represents a carboxyl group.
 10. A compound as claimed in claim 3wherein R² and R⁴ each represent a carboxyl group and R³ represents ahydrogen atom.
 11. A compound as claimed in claim 3 wherein R²represents a carboxyl group, R³ represents an isopropyl group and R⁴represents a hydrogen atom.
 12. A compound as claimed in claim 3 whereinR² represents a carboxyl group, and R³ and R⁴ each represent a hydrogenatom.
 13. A compound as claimed in claim 3 wherein R² represents acarboxyl group, and R³ and R⁴ each represent a methyl group.
 14. Acompound as claimed in claim 3 wherein R² represents a methyl group, R³represents a carboxyl group and R⁴ represents a hydrogen atom.
 15. Acompound as claimed in claim 3 wherein R² represents a methoxycarbonylgroup, R³ represents a methyl group and R⁴ represents a hydrogen atom.16. A compound as claimed in claim 3 wherein R² represents a hydrazinocarbonyl group, R³ represents a methyl group and R⁴ represents ahydrogen atom.
 17. A compound as claimed in claim 3 wherein R²represents a carboxyl group, R³ represents a hydroxy group and R⁴represents a hydrogen atom.
 18. A compound as claimed in claim 3 whereinR² and R⁴ each represent a hydrogen atom and R³ represents a methoxygroup.
 19. A compound as claimed in claim 3 wherein R² represents anamino group, R³ represents a methyl group and R⁴ represents a hydrogenatom.
 20. A compound as claimed in claim 3 wherein R² represents ahydroxysulfonyl group, R³ represents a methyl group and R⁴ represents ahydrogen atom.
 21. A compound as claimed in claim 3 wherein R² and R⁴each represent a hydrogen atom and R³ represents a chlorine atom.
 22. Acompound as claimed in claim 1 which is represented by the formula (Ib):##STR38##
 23. A compound as claimed in claim 22 wherein R¹² represents ahydrogen atom.
 24. A compound as claimed in claim 22 wherein R¹²represents a benzoyl group.
 25. A compound as claimed in claim 22wherein R¹² represents a 2-furancarbonyl group.
 26. A compound asclaimed in claim 22 wherein R¹² represents a 2-thiophenecarbonyl group.27. A compound as claimed in claim 22 wherein R¹² represents a3-pyridinecarbonyl group.
 28. A compound as claimed in claim 22 whereinR¹² represents a 2-pyrrolecarbonyl group.
 29. A compound as claimed inclaim 22 wherein R¹² represents a 3,4-methylenedioxybenzoyl group.
 30. Acompound as claimed in claim 22 wherein R¹² represents acyanomethylthioacetyl group.
 31. A compound as claimed in claim 22wherein R¹² represents a 3,4-diacetoxybenzoyl group.
 32. A compound asclaimed in claim 22 wherein R¹² represents a 3,4,5-triacetoxybenzoylgroup.
 33. A compound as claimed in claim 1 which is represented by theformula (Ic): ##STR39##
 34. A compound as claimed in claim 33 wherein R⁵represents a methyl group and R⁶ represents a hydrogen atom.
 35. Acompound as claimed in claim 33 wherein R⁵ represents a hydrogen atomand R⁶ represents a carboxyl group.
 36. A compound as claimed in claim33 wherein R⁵ represents a hydrogen atom and R⁶ represents anethoxycarbonyl group.
 37. A compound as claimed in claim 33 wherein R⁵represents a hydrogen atom and R⁶ represents a piperidinocarbonyl group.38. A compound as claimed in claim 1 which is represented by the formula(Id): ##STR40##
 39. A compound as claimed in claim 38 wherein R⁷represents a hydrogen atom.
 40. A compound as claimed in claim 38wherein R⁷ represents a methyl group.
 41. A compound as claimed in claim1 which is represented by the formula (Ie): ##STR41##
 42. A compound asclaimed in claim 1 which is represented by the formula (If): ##STR42##43. A compound as claimed in claim 42 wherein R⁸ represents a hydrogenatom and R⁹ represents a carboxyl group.
 44. A compound as claimed inclaim 42 wherein R⁸ represents a hydrogen atom and R⁹ represents anamino group.
 45. A compound as claimed in claim 42 wherein R⁸ representsa hydrogen atom and R⁹ represents a methyl group.
 46. A compound asclaimed in claim 42 wherein R⁸ represents a carboxyl group and R⁹represents a methyl group.
 47. A compound as claimed in claim 1 which isrepresented by the formula (Ih): ##STR43##
 48. A compound as claimed inclaim 47 wherein R¹⁰ represents a methyl group and R11 represents ahydrogen atom.
 49. A compound as claimed in claim 47 wherein R¹⁰represents a hydrogen atom and R¹¹ represents a carboxyl group.
 50. Acompound as claimed in claim 1 which is at least one of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)-thiomethyl]8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid and salts, hydrates and hydrates ofsalts of said cephalosporin compound.
 51. A compound as claimed in claim1 which is at least one of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]8-oxo-5-thia-1-aza-bicyclo-[4.2.0]oct-2-ene-2-carboxylicacid and salts, hydrates and hydrates of salts of said cephalosporincompound.
 52. A compound as claimed in claim 1 which is at least one of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]3-[(6-carboxy-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and salts, hydrates and hydrates ofsalts of said cephalosporin compound.
 53. A compound as claimed in claim1 which is at least one of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]3-[(2-carboxymethyl-5-methyl-s-triazolo-[1,5-a]pyrimidin-7-yl)thiomethyl]8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and salts, hydrates and hydrates ofsalts of said cephalosporin compound.
 54. A compound as claimed in claim1 which is at least one of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(5-carboxymethyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and salts, hydrates and hydrates ofsalts of said cephalosporin compound.
 55. A compound as claimed in claim1 which is at least one of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]3-[(5-carboxy-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and salts, hydrates and hydrates ofsalts of said cephalosporin compound.
 56. A compound as claimed in claim1 which is at least one of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]3-[(2,6-dicarboxy-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid and salts, hydrates and hydrates of salts of said cephalosporincompound.
 57. A compound as claimed in claim 1 which is at least one of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-hydroxyimino)acetamido]3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylicacid and salts, hydrates and hydrates of salts of said cephalosporincompound.
 58. A compound as claimed in claim 1 which is at least one of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-benzoyloxyimino)acetamido]3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylicacid and salts, hydrates and hydrates of salts of said cephalosporincompound.
 59. A compound as claimed in claim 1 which is at least one of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-(2-furancarbonyl)oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo- [1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo [4.2.0]oct-2-ene-2-carboxylic acid and salts,hydrates and hydrates of salts of said cephalosporin compound.
 60. Acompound as claimed in claim 1 which is at least one of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-(2-thiophenecarbonyl)-oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and salts,hydrates and hydrates of salts of said cephalosporin compound.
 61. Acompound as claimed in claim 1 which is at least one of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-(3-pyridinecarbonyl)-oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidon-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and salts,hydrates and hydrates of salts of said cephalosporin compound.
 62. Acompound as claimed in claim 1 which is at least one of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-(2-pyrrolecarbonyl)oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo-[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo oct-2-ene-2-carboxylic acid and salts, hydratesand hydrates of salts of said cephalosporin compound.
 63. A compound asclaimed in claim 1 which is at least one of (6R,7R)-7-[2-(2amino-4-thiazolyl)-2-[Z-(3,4-methylenedioxy-benzoly)oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid and salts, hydrates and hydrates of salts of said cephalosporincompound.
 64. A compound as claimed in claim 1 which is at least one of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-cyanomethylthioacetyl-oxyimino)acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and salts,hydrates and hydrates of salts of said cephalosporin compound.
 65. Acompound as claimed in claim 1 which is at least one of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-(3,4-diacetoxybenzoyl-oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and salts,hydrates and hydrates of salts of said cephalosporin compound.
 66. Acompound as claimed in claim 1 which is at least one of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[Z-(3,4,5-triacetoxybenzoyl)oxyimino]acetamido]-3-[(2-carboxy-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid and salts, hydrates and hydrates of salts of said cephalosporincompound.
 67. A compound as claimed in claim 1 which is at least one of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(2-carboxy-5-isopropyl-s-triazolo[1,5-a]-pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid and salts,hydrates and hydrates of salts of said cephalosporin compound.
 68. Acompound as claimed in claim 1 which is at least one of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(2-carboxy-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid and salts, hydrates and hydrates of salts of said cephalosporincompound.
 69. A compound as claimed in claim 1 which is at least one of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(2-carboxy-5,6-dimethyl-s-triazolo[1,5-a]-pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid and salts,hydrates and hydrates of salts of said cephalosporin compound.
 70. Acompound as claimed in claim 1 which is at least one of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(5-carboxy-2-methyl-s-triazolo[1,5-a]-pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid and salts, hydrates and hydrates of salts of said cephalosporincompound.
 71. A compound as claimed in claim 1 which is at least one of(6R,7R) -7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[2-methoxycarbonyl-5-methyl-s-triazolo-[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and salts,hydrates and hydrates of salts of said cephalosporin compound.
 72. Acompound as claimed in claim 1 which is at least one of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(2hydrazinocarbonyl-5-methyl-s-triazolo-[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-carboxylic acid and salts, hydratesand hydrates of salts of said cephalosporin compound.
 73. A compound asclaimed in claim 1 which is at least one of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)actamido]-3-[(2-carboxy-5-hydroxy-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1azabicyclo-[4.2.0oct-2-ene-2-carboxylic acid and salts, hydrates and hydrates of salts ofsaid cephalosporin compound.
 74. A compound as claimed in claim 1 whichis at least one of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(5-methoxy-s-triazolo[1,5-a]pyrimidin-7yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid and salts, hydrates and hydrates of salts of said cephalosporincompound.
 75. A compound as claimed in claim 1 which is at least one of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(2-amino-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylicacid and salts, hydrates and hydrates of salts of said cephalosporincompound.
 76. A compound as claimed in claim 1 which is at least one of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(2-cyano-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylicacid and salts, hydrates and hydrates of salts of said cephalosporincompound.
 77. A pharmaceutical composition as claimed in claim 1 whichis at least one of (6R,7R)-7-[2-(2amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(2-hydroxysulfonyl-5-methyl-s-triazolo-[1,5-pyrimidin-7-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid and salts, hydrates and hydrates of salts of said cephalosporincompound.
 78. A compound as claimed in claim 1 which is at least one of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(5-chloro-s-triazolo[1,5-a]pyrimidin-7-yl)-thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid and salts, hydrates and hydrates of salts of said cephalosporincompound.
 79. A compound as claimed in claimed in claim 1 which is atleast one of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(7-hydroxy-5-methyl-s-triazolo[1,5-a]pyrimidin-2-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylicacid and salts, hydrates and hydrates of salts of said cephalosporincompound.
 80. A compound as claimed in claim 1 which is at least one of(6R,7R) -7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(6-carboxy-7-hydroxy-s-triazolo[1,5,-a]pyrimidin-2-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid and salts,hydrates and hydrates of salts of said cephalosporin compound.
 81. Acompound as claimed in claim 1 which is at least one of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(6-ethoxycarbonyl-7-hydroxy-s-triazolo-[1,5-a]pyrimidin-2-yl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and salts, hydratesand hydrates of salts of said cephalosporin compound.
 82. A compound asclaimed in claim 1 which is at least one of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[7-hydroxy-6-piperidinocarbonyl-s-triazolo[1,5,-a]pyrimidin-2-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid and salts, hydrates and hydrates of salts of said cephalosporincompound.
 83. A compound as claimed in claim 1 which is at least one of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(7-carboxy-s-triazolo[4,3-a]pyrimidin-5-thiomethyl]-8-oxo-5-thia-1azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid and salts, hydrates and hydrates of salts of said cephalosporincompound.
 84. A compound as claimed in claim 1 which is at least one of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(7-carboxy-3-methyl-s-traizolo[4,3,-a]pyrimidin-5-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylicacid and salts, hydrates and hydrates of salts of said cephalosporincompound.
 85. A compound as claimed in claim 1 which is at least one of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(7-carboxy-5-hydroxy-s-triazolo[4.2.0]-pyrimidin-3-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylicacid and salts, hydrates and hydrates of salts of said cephalosporincompound.
 86. A compound as claimed in claim 1 which is at least one of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(7-carboxy-s-triazolo[1,5-c]pyrimidin-5-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid and salts, hydrates and hydrates of salts of said cephalosporincompound.
 87. A compound as claimed in claim 1 which is at least one of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(7-amino-s-triazolo[1,5-c]pyrimidin-5yl)-thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid and salts, hydrates and hydrates of salts of said cephalosporincompound.
 88. A compound as claimed in claim 1 which is at least one of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(7-methyl-s-triazolo[1,5-c]pyrimidin-5-yl)-thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid and salts, hydrates and hydrates of salts of said cephalosporincompound.
 89. A compound as claimed in claim 1 which is at least one of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(2-carboxy-7-methyl-s-triazolo[1,5,-c]pyrimidin-5-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylicacid and salts, hydrates and hydrates of salts of said cephalospor incompound.
 90. A compound as claimed in claim 1 which at least one of(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(7-methyl-5-oxo-5H-1,3,4-thiadiazolo-[3,2-a]pyrimidin-2-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carbosylic acid and salts, hydrates and hydrates of salts ofsaid cephalosporin compound.
 91. A compound as claimed in claim 1 whichis at least one of (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)acetamido]-3-[(6-carboxy-5-oxo-5H-1,3,4-thiadiazolo-[3,2,-a]pyrimidin-2-yl)thiomethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid and salts, hydrates and hydrates of salts of said cephalosporincompound.
 92. An antibiotic composition comprising a mixture of two ormore compounds of claim 1 and salts, hydrates and hydrates of salts ofsaid cephalosporin compound and a pharmaceutically acceptable carrier.93. An antibiotic composition comprising a pharmaceutically effectiveamount of a compound of claim 1 or salts, hydrates and hydrates of saltsof said cephalosporin compound and a pharmaceutically acceptablecarrier.
 94. A method of treating infectious diseases comprisingadministering an infectious disease treating effective amount of theantibiotic composition of claim 93 to a patient infected by aninfectious disease.